Ortho substituted aromatic compounds useful as antagonists of the pain enhancing effects of E-type prostaglandins

ABSTRACT

The invention relates to compounds of the formula (I): ##STR1## wherein A, B and D are various ring systems such as phenyl, R 1  includes carboxy, R 3  is hydrogen or C 1-4  alkyl and Z is a linking group such as --(CH(R 5 )) m  -- wherein m is 2, 3 or 4, and R 5  includes hydrogen and methyl; and pharmaceutically acceptable salts and in vivo hydrolysable esters or amides thereof, processes for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of pain.

This invention relates to novel, aromatic compounds andpharmaceutically-acceptable salts thereof which possess usefulpharmacological properties. More particularly the compounds of theinvention are antagonists of the pain enhancing effects of E-typeprostaglandins. The invention also relates to processes for themanufacture of the aromatic compounds and pharmaceutically-acceptablesalts thereof; to novel pharmaceutical compositions containing them; andto use of the compounds in pain relief.

The compounds of the invention are useful in the treatment of pain suchas the pain associated with joint conditions (such as rheumatoidarthritis and osteoarthritis), postoperative pain, post-partum pain, thepain associated with dental conditions (such as dental caries andgingivitis), the pain associated with burns (including sunburn), thetreatment of bone disorders (such as osteoporosis, hypercalcaemia ofmalignancy and Paget's disease), the pain associated with sportsinjuries and sprains and all other painful conditions in which E-typeprostaglandins wholly or in part play a pathophysiological role.

Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the mainclasses of drugs in pain relief. However both possess undesireable sideeffects. NSAIDS are known to cause gastrointestinal irritation andopiates are known to be addictive.

We have now found a class of compounds structurally different to NSAIDSand opiates, and useful in the relief of pain.

The compounds of the invention may also possess anti-inflammatory,anti-pyretic and anti-diarrhoeal properties and be effective in otherconditions in which prostaglandin E₂ (PGE₂) wholly or in part plays apathophysiological role.

According to the invention there is provided a compound of the formulaI; ##STR2## wherein: A is optionally substituted: phenyl, naphthyl or a5- or 6-membered heteroaryl ring system containing no more than two ringnitrogen atoms or thiadiazolyl or a bicyclic ring system of the formula:##STR3## wherein E is nitrogen or CH, F is nitrogen or CH, G is sulphuror oxygen and H is nitrogen or CH;

wherein the --Z-- and --OCH(R³)-- groups are positioned in a 1,2relationship to one another on ring carbon atoms;

and provided that the ring atom in the 2-position relative to the ringcarbon atom bearing the --OCH(R³)-- group and in the 3-position relativeto the ring carbon atom bearing the --Z--B--R¹ group is unsubstitutedand, when A is naphthyl, either the --Z--B--R¹ group is in the1-position and the --OCH(R³)-- group is in the 2-position of thenaphthyl group and the ring atom in the 3-position is not substituted,or the --Z--B--R¹ -- group is in the 2-position and the --OCH(R³)--group is in the 3-position of the naphthyl group and the ring atom inthe 4-position is not substituted (according to the IUPAC system);

B is an optionally substituted 5- or 6-membered heteroaryl ring system,optionally substituted phenyl or an optionally substituted ring systemof the formula: ##STR4## wherein 0 or 1 of J and K are ring nitrogenatoms and the remainder are ring carbon atoms and R⁴ is C₁₋₆ alkyl;

wherein the --Z--A and --R groups are positioned an either a 1,3 or a1,4 relationship to one another on ring carbon atoms in B in 6 memberedrings and in a 1,3 relationship to one another in ring carbon atoms in Bin 5-membered rings;

D is optionally substituted: phenyl or a 5- or 6- membered heteroarylring system;

R¹ is carboxy, optionally substituted tetrazolyl, carboxyC₁₋₄ alkyl,optionally substituted tetrazolylC₁₋₄ alkyl, hydroxamic acid, sulphonicacid, tetronic acid or a pharmaceutically acceptable amide (--CONR--),reverse amide (--NRCC--), acylsulphonamide (--CONRSO₂ --), acylhydrazide(--CON(R)N ) or C₁₋₄ alkyl substituted by a pharmaceutically-acceptableamide, reverse amide, acylsulphonamide or acylhydrazide or R¹ is of theformula (IIA), (IIB) or (IIC): ##STR5## wherein X is CH or nitrogen, Yis oxygen or NH, Z is CH₂, NH or oxygen and Y¹ is oxygen or sulphurprovided that there is no more than one ring oxygen and there are atleast two ring heteroatoms;

R³ is hydrogen or C₁₋₄ alkyl;

Z is of the formula --(CH(R⁵))_(m) --, --(CHR⁵)_(p) CR⁵ ═CR⁵ (CHR⁵)_(q)--, --(CHR⁵)_(r) C(═O)CR⁵ ═CR⁵ (CHR⁵)_(S) -- or --(CHR⁵_(t))C(═O)(CHR⁵)_(u) --, wherein m is 2, 3 or 4, p and q areindependently 0, 1 or 2 providing p+q is not greater than 2, one of rand s is 0 and the other is 1 and t and u are independently 0, 1, 2 or 3providing t+u is not less than 1 or greater than 3;

and R⁵ is hydrogen, methyl, ethyl, hydroxy, methoxy or ethoxy;

and N-oxides where chemically possible;

and S-oxides where chemically possible;

and pharmaceutically acceptable salts and in vivo hydrolysable estersand amides thereof.

Particular pharmaceutically acceptable amides are, for example, of theformula --CONR⁶ R⁷ wherein R⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ cyclcalkylC₁₋₃ alkyl, C₅₋₇ cycloalkenyl or C₅₋₇ cycloalkenylC₁₋₃alkyl and R⁷ is hydrogen, C₁₋₆ alkoxycarbonyl, hydroxy or optionallysubstituted: C₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkylC₁₋₆ alkyl, C₃₋₇ cycloalkylC₂₋₆ alkenyl, C₃₋₇cycloalkylC₂₋₆ alkynyl, C₅₋₇ cycloalkenyl, C₃₋₇ cycloalkenylC₁₋₆ alkyl,C₅₋₇ cycloalkenylC₂₋₆ alkenyl, C₅₋₇ cycloalkenylC₂₋₆ alkyryl, 5- or6-membered heteroaryl, 5- or 6-membered heteroarylC₁₋₆ alkyl, 5- or6-membered saturated or partially saturated heterocyclyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₆ alkyl, 5-or 6-membered heteroarylium or 5- or 6-membered heteroaryliumC₁₋₆ alkyl;or wherein R⁶ and R⁷ together with the amide nitrogen to which they areattached (NR⁶ R⁷) form an amino acid residue or ester thereof. Examplesof 5- or 6-membered heteroarylium rings are pyridinium, pyriminidinium,pyrazinium, pyridazinium and imidazolium.

Particular pharmaceutically acceptable reverse amides are, for example,of the formula --NR⁶ COR⁸ wherein R⁶ is as hereinabove defined and R⁸ isof the formula OR⁹ wherein R⁹ is hydrogen, optionally substituted C₁₋₆alkyl, 5- or 6-membered monocyclic heteroaryl or a 5- or 6-memberedmonocyclic saturated or partially saturated heterocyclyl, or R⁸ is offormula NR¹⁰ R¹¹ wherein R¹⁰ is hydrogen or C₁₋₆ alkyl and R¹¹ isoptionally substituted C₁₋₆ alkyl or R⁸ is optionally substituted C₁₋₆alkyl; and wherein ring systems are optionally substituted.

Particular pharmaceutically acceptable acyl sulphonamides are, forexample of the formula --CONR⁶ SO₂ R¹² wherein R⁶ is as hereinabovedefined and R¹² is optionally substituted: C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₃₋₇cycloalkylC₂₋₆ alkenyl, C₃₋₇ cycloalkylC₂₋₆ alkynyl, C₅₋₇ cycloalkenyl,C₃₋₇ cycloalkenylC₁₋₆ alkyl, C₅₋₇ cycloalkenylC₂₋₆ alkenyl, C₅₋₇cycloalkenylC₂₋₆ alkynyl, 5- or 6-membered heteroaryl, 5- or 6-memberedheteroylarylC₁₋₆ alkyl, phenyl, phenylC₁₋₆ alkyl, 5- or 6-memberedsaturated or partially saturated heterocyclyl, 5- or 6-memberedsaturated or partially saturated heterocyclylC₁₋₆ alkyl, 8-10 memberedheteroarylC₁₋₆ alkyl or 5- or 6-membered heteroaryliumC₁₋₄ alkyl

Particular acylhydrazides are, for example of the formula --CONR₆N(R¹⁶)R¹⁷ wherein R⁶ is as hereinabove defined, R¹⁶ is hydrogen or C₁₋₆alkyl and R¹⁷ is hydrogen, hydroxy or optionally substituted: C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₆ alkyl, C₃₋₇ cycloalkylC₂₋₆ alkenyl, C₃₋₇ cycloalkylC₂₋₆alkynyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₆ alkyl, C₅₋₇cycloalkenylC₂₋₆ alkenyl, C₅₋₇ cycloalkenylC₂₋₆ alkynyl, 5- or6-membered heteroaryl, 5- or 6-membered heteroarylC₁₋₆ alkyl, 5- or6-membered saturated or partially saturated heterocyclyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₆ alkyl, orR¹⁶ and R¹⁷, together with the nitrogen atom to which they are attached,form a 4 to 8-membered saturated or partially saturated heterocyclicring or form an amino acid residue or ester thereof.

A 5- or 6-membered heteroaryl ring system is a monocyclic aryl ringsystem having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms areselected from nitrogen, oxygen and sulphur.

A 5- or 6-membered saturated or partially saturated heterocyclyl is aring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ring atomsare selected from nitrogen, oxygen and sulphur.

A 4 to 8-membered saturated or partially saturated heterocyclic ring isa ring system having 4 to 8 ring atoms wherein 1, 2 or 3 of the ringatoms are selected from nitrogen, oxygen and sulphur.

Particular 5- or 6-membered heteroaryl rings include pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl andoxazolyl.

Particular 5- or 6-membered saturated or partially saturatedheterocyclic ring ring systems include pyrrolidinyl, pyrrolinyl,imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.

An 8-10 bicyclic heteroaryl is a bicyclic aryl ring system having 8 to10 ring atoms wherein 1, 2, 3 or 4 ring atoms are selected fromnitrogen, oxygen and sulphur.

Examples of suitable optional substituents for C₁₋₆ alkyl in amides,reverse amides, acylsulphonamides and acylhydrazides are hydroxy, amino,C₁₋₄ alkoxy, halo, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylS(O)_(p) -- (p is 0, 1or 2), cyano, carboxy, C₁₋₄ alkanoyl, C₁₋₄ alkanoylamino,trifluoromethyl, pentafluoroethyl, nitro, C₃₋₇ cycloalkyl, phenyl, 5- or6-membered monocyclic heteroaryl, tetrazolyl, a 5- or 6-memberedsaturated or partially saturated heterocyclic ring and 5- or 6-memberedmonocyclic heteroarylium.

Particular substituents for ring systems in amides and reverse amidesinclude, halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C₁₋₄alkylS(O)_(p) -- (p is 0, 1 or 2), carbamoyl, C₁₋₄ alkanoylamino, C₁₋₄alkanesulphonamido and, when the ring system contains a saturated ringcarbon (--CH₂ --), oxo, hydroxyimino and C₁₋₄ alkoxyimino.

Suitable ring systems of the formula (IIA), (IIB) or (IIC) include5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl, 3-oxo-2,3-dihydro-1,2,4-oxadiazole-5-yl, 3-thioxo-2,3-dihydro-1,2,4-oxadiazole-5-yl,5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-yl,5-oxo-4,5-dihydro-1,2,4-triazole-3-yl, 3-oxo-2,3-dihydroisoxazole-5-yl,5-oxo-1,5-dihydroisoxazole-3-yl and 5-oxo-2,3-dihydropyrazol-3-yl.

Amino acid residues formed from R⁶ and R⁷ or R¹⁶ and R¹⁷ together withthe amide nitrogen to which they are attached and esters thereof includefor example radicals of the formula --NH--CH(R^(c))--COOR^(d) whereinR^(c) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,phenylC₋₃ alkyl, 5- or 6-membered heteroaryl or 5- or 6-memberedheteroarylC₁₋₃ alkyl and R^(d) is hydrogen or C₁₋₆ alkyl, wherein alkyl,alkenyl, alkynyl, phenyl and heteroaryl groups are optionallysubstituted. Examples of substituents include those mentioned above forring A. In particular hydroxy.

Particular substituents for ring carbon atoms in A, include halo,trifluoromethyl, nitro, hydroxy, amino, C₁₋₄ alkylamino, di C₁₋₄alkyl!amino, cyano, C₁₋₆ alkoxy, carboxy, allyloxy, C₁₋₆ alkylS(O)_(p)-- (p is 0, 1 or 2), phenylS(O)_(p) -- (p is 0, 1 or 2), trifluoromethylS(O)_(p) -- (p is 0, 1 or 2) C₁₋₆ alkyl (optionally substituted byhydroxy, C₁₋₄ alkoxy, amino, halo, nitro, C₁₋₄ alkylS(O)_(p) -- (p is 0,1 or 2), phenyl(O)_(p) -- (p is 0, 1 or 2) or cyano), carbamoyl, C₁₋₄alkylcarbamoyl, di(C₁₋₄ alkyl)carbamoyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkylC₁₋₃ alkyl, C₃₋₇ cycloalkylC₂₋₃ alkenyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenylC₂₋₃ alkenyl, benzyl, benzoyl, benzyloxy,C₁₋₄ alkoxycarbonylamino, C₁₋₄ alkanoylamino, (wherein the alkanoylgroup is optionally substituted by hydroxy), C₁₋₄ alkanoyl(N--C₁₋₄alkyl)amino (wherein the alkanoyl group is optionally substituted byhydroxy), C₁₋₄ alkanesulphonamido, benzenesulphonamido, aminosulphonyl,C₁₋₄ alkylaminosulphonyl, di(C₁₋₄ alkyl)aminosulphonyl, C₁₋₄alkoxycarbonyl, C₂₋₄ alkanoyloxy, C₁₋₆ alkanoyl, formylC₁₋₄ alkyl,trifluoroC₁₋₃ alkylsulphonyl, 1-(hydroxyimino)-1(phenyl)methyl, 1-(C₁₋₄alkoxyimino)-1-(phenyl)methyl, hydroxyiminoC₁₋₆ alkyl, C₁₋₄alkoxyiminoC₁₋₆ alkyl, C₁₋₆ alkylcarbamoylamino, C₂₋₆ alkenyl(substituted by halo), N-(amino)iminoC₁₋₄ alkyl, N-(C₁₋₄alkylamino)iminoC₁₋₄ alkyl, N- di(C₁₋₄ alkyl)amino!iminoC₁₋₄ alkyl,N-(phenyl)aminoiminoC₁₋₄ alkyl and 5-membered heteroaryl containing 1 or2 heteroatoms selected from nitrogen, oxygen and sulphur and, when A isphenyl or a 6-membered heteroaryl ring having ring carbon atoms in the4-position in relation to the --O--CH(R⁴)-- substitutent and in the4-position in relation to the --Z--B--R¹ substitutent, suitablesubstitutents include tetramethylene and diradicals of the formula--(CH₂)₃ CO--, --(CH₂)₃ C(═N--OH)-- and --(CH₂)₃ C(═N--OC₁₋₄ alkyl)--,wherein the left hand side of the diradical is attached to the a carbonatom in the 4-position in relation to the --O--CH(R⁴)-- substitutent andthe right hand side of the diradical is attached to a carbon atom in the4-position in relation to the --Z--B--R¹ substitutent.

Particular substituents for ring carbon atoms in B include halo,trifluoromethyl, nitro, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, amino, C₁₋₆alkylamino, di(C₁₋₄ alkyl)amino, cyano, --S(O)_(p) C₁₋₆ alkyl (p is 0, 1or 2), C₁₋₄ alkanoylamino, benzenesulphonamido, C₁₋₄ alkanesulphonamido,C₁₋₆ alkoxycarbonylamino, carbamoyl, C₁₋₄ alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl.

Particular optional substituents for D are halo, trifluoromethyl, nitro,hydroxy, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄alkanoylamino, cyano, C₁₋₆ alkoxy, allyloxy, --S(O)_(p) C₁₋₄ alkyl (p is0, 1 or 2), C₁₋₄ alkanoyl or C₁₋₄ alkyl optionally substituted byhydroxy, halo, nitro, cyano and amino.

Particular substituents for tetrazole groups include C₂₋₆ alkanoyloxyand C₁₋₆ alkyl.

Where a ring nitrogen atom in A, B or D can be substituted withoutbecoming quaternised, it is unsubstituted or substituted by C₁₋₄ alkyl.

The term alkyl when used herein includes straight chain and branchedchain substituents for example methyl, ethyl, n-propyl, isopropyl,n-butyl and isobutyl. The same convention applies to other radicals, forexample hydroxyiminoC₁₋₆ alkyl includes 1-(hydroxyimino)ethyl and2-(hydroxyimino)ethyl.

The invention also includes tautomers. For example 2-hydroxypyridineincludes 2-pyridone.

Examples of C₁₋₆ alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl andt-butoxycarbonyl; examples of carboxyC₁₋₃ alkyl are carboxymethyl,2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C₁₋₆alkoxycarbonylC₁₋₃ alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyland methoxycarbonylethyl; examples of tetrazolylC₁₋₃ alkyl aretetrazolylmethyl and 2-tetrazolylethyl, examples of C₁₋₄ alkoxy aremethoxy, ethoxy, propoxy and isopropoxy; examples of C₂₋₆ alkenyl arevinyl and allyl; examples of C₂₋₆ alkynyl are ethynyl and propynyl;examples of C₁₋₄ alkanoyl are formyl, acetyl, propionyl and butyryl;examples of halo are fluoro, chloro, bromo and iodo; examples of C₁₋₄alkylamino are methylamino, ethylamino, propylamino and isopropylamino;examples of di(C₁₋₄)alkyl)amino are dimethylamino, diethylamino andethylmethylamino; examples of --S(O)_(p) C₁₋₄ alkyl are methylthio,methylsulphinyl and methylsulphonyl; examples of C₁₋₄ alkylcarbamoyl aremethylcarbamoyl and ethylcarbamoyl; examples of di(C₁₋₄ alkyl)carbamoylare dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl;examples of C₁₋₆ alkyl are methyl, ethyl, propyl and isopropyl; examplesof C₃₋₇ cycloalkyl are cyclopropyl, cyclobutyl and cyclohexyl; examplesof C₃₋₇ cycloalkylC₁₋₃ alkyl are cyclopropylmethyl and cyclohexylmethyl;examples of C₃₋₇ cycloalkylC₂₋₃ alkenyl are cyclopropylethenyl andcyclopentylpropenyl; examples of C₃₋₇ cycloalkylC₂₋₃ alkynyl arecyclopropylethynyl and cyclopentylethynyl; examples of C₅₋₇ alkenyl arecyclopentenyl and cyclohexenyl; examples of C₅₋₇ cycloalkenylC₁₋₃ alkylare cyclopentenylmethyl and cyclohexenylmethyl; examples of C₅₋₇cycloalkenylC₂₋₃ alkenyl are cyclohexenylethenyl andcycloheptenylethenyl; examples of C₅₋₇ cycloalkenylC₂₋₃ alkynyl arecyclopentenylethynyl and cyclohexenylethynyl; examples of C₁₋₄alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino;examples of C₁₋₄ alkanoylamino are acetamido and propionamido; examplesof C₁₋₄ alkanoyl(N--C₁₋₄ alkyl)amino are N-methylacetamido andN-methylpropionamido; examples of C₁₋₄ alkanesulphonamido aremethanesulphonamido and ethanesulphonamido; examples of C₁₋₄alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl;examples of di(C₁₋₄ alkyl)aminosulphonyl are dimethylaminosulphonyl,diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C₁₋₄alkanoyloxy are acetyloxy and propionyloxy; examples of formylC₁₋₄ alkylare formylmethyl and 2-formylethyl; examples of hydroxyiminoC₁₋₆ alkylare hydroxyiminomethyl and 2-(hydroxyimino)ethyl; and examples of C₁₋₄alkoxyiminoC₁₋₆ alkyl are methoxyiminomethyl, ethoxyiminomethyl and2-(methoxyimino)ethyl.

Preferably A is optionally substituted:

phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl,thienyl, thiadiazolyl or thiazolyl.

Preferably ring systems of the formula (IA) are of the formula: ##STR6##wherein J; K and R⁴ are as hereinabove defined.

Preferably ring systems of the formula (IB) are of the formula: ##STR7##wherein J, K and R⁴ are as hereinabove defined.

Preferably ring systems of the formula (IC) are of the formula: ##STR8##wherein J, K and R⁴ are as hereinabove defined.

More preferably ring systems of the formula (IA) are N--C₁₋₄alkyl-2-oxo-1,2-dihydropyridin-3,6-diyl or 3-(C₁₋₄alkyl)-4-oxo-3,4-dihydropyridin-2,5-diyl.

More preferably ring systems of the formula (IB) are N--C₁₋₄alkyl-4-oxo-1,4-dihydropyridin-2,5-diyl.

Preferably R⁴ is methyl.

Preferably B is optionally substituted: phenyl, pyridyl, thiazolyl,thienyl, thiadiazolyl, imidazolyl, oxazolyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyridone, pyridazinone, furan, pyrrole or pyrimidinone.

Preferably D is phenyl, thienyl, furyl, pyridyl, thiazolyl or oxazolyl.

More preferably A is optionally substituted: phenyl, thienyl naphthyl orthiadiazolyl.

Yet more preferably A is optionally substituted: phenyl, thienyl ornaphthyl.

More preferably B is optionally substituted pyridyl, phenyl, thiazolyl,thienyl, pyrazinyl, oxazolyl, pyridazinyl or 2-pyridone optionallysubstituted on the ring nitrogen by a methyl group.

More preferably D is optionally substituted: phenyl, thienyl or furyl.

Preferably when D is phenyl it is unsubstituted or substituted in themeta- or para- position.

Most preferably A is optionally substituted phenyl.

Most preferably B is optionally substituted: phenyl, pyridyl, or2-pyridone optionally substituted on the ring nitrogen by a methylgroup.

Most preferably D is optionally substituted phenyl.

Preferably R¹ is optionally substituted tetrazolyl, carboxyC₁₋₄ alkyl,optionally substituted tetrazolylC₁₋₄ alkyl, hydroxamid acid, sulphonicacid, tetronic acid or a pharmaceutically acceptable amide, reverseamide, acylsulphonamide or C₁₋₄ alkyl substituted by apharmaceutically-acceptable amide, reverse amide or acylsulphonamide.

Preferably pharmaceutically acceptable amides are, of the formula--CONR⁶ R⁷ wherein R⁶ is hydrogen or C₁₋₆ alkyl and R⁷ is hydrogen, C₁₋₆alkoxycarbonyl, hydroxy, optionally substituted C₁₋₆ alkyl, C₃₋₇cycloalkyl, phenyl, tetrazolyl, 5- or 6-membered heteroaryl, 5- or6-membered monocylic saturated or partially saturated heterocyclyl and5- or 6-membered heteroarylium, 5- or 6-membered monocyclicheteroarylC₁₋₄ alkyl, 5- or 6- membered saturated or partially saturatedheterocyclylC₁₋₄ alkyl, 8-10 membered bicyclic heteroarylC₁₋₄ alkyl, 5-or 6-membered heteroaryliumC₁₋₄ alkyl or C₃₋₇ cycloalkylC₁₋₄ alkyl,wherein ring systems are optionally substituted. Examples of 5- or6-membered heteroarylium rings are pyridinium, pyriminidinium,pyrazinium, pyrazinium, and imidazolium.

Preferably pharmaceutically acceptable reverse amides are of the formula--NR⁶ COR⁸ wherein R⁶ is as hereinabove defined and R⁸ is of the formulaOR⁹ wherein R⁹ is hydrogen, optionally substituted C₁₋₆ alkyl, 5- or6-membered heteroaryl or a 5- or 6-membered saturated or partiallysaturated heterocyclyl, or R⁸ is of formula NR¹⁰ R¹¹ wherein R¹⁰ ishydrogen or C₁₋₆ alkyl and R¹¹ is optionally substituted C₁₋₆ alkyl orR⁸ is optionally substituted C₁₋₆ alkyl; and wherein ring systems areoptionally substituted.

Preferably pharmaceutically acceptable acyl sulphonamides are of theformula --CONR⁶ SO₂ R¹² wherein R⁶ is as hereinabove defined and R¹² isoptionally substituted: C₁₋₆ C alkyl, phenyl, 5- or 6-memberedmonocyclic heteroaryl, 5- or 6-membered monocyclic saturated orpartially saturated heterocyclyl, 5- or 6-membered heteroarylC₁₋₄ alkyl,5- or 6-membered saturated or partially saturated heterocyclylC₁₋₄alkyl, 8-10 membered bicyclic heteroarylC₁₋₄ alkyl, 5- or 6-memberedheteroaryliumC₁₋₄ alkyl or C₃₋₇ cycloalkylC₁₋₄ alkyl.

More preferably R¹ is carboxy, optionally substituted tetrazolyl,carboxymethyl, optionally substituted tetrazolylmethyl, hydroxamic acid,sulphonic acid, tetronic acid or of the formula --CONR⁶ R⁷ or of theformula --CH₂ CONR⁶ R⁷ wherein R⁶ is hydrogen or C₁₋₄ alkyl and R⁷ ishydrogen, C₁₋₆ alkoxycarbonyl, hydroxy, optionally substituted: C₁₋₆alkyl, cyclopropylC₁₋₄ alkyl, cyclobutylC₁₋₄ alkyl, cyclopenylC₁₋₄alkyl, cyclohexylC₁₋₄ alkyl, pyridylC₁₋₄ alkyl, pyrimidylC₁₋₄ alkyl,pyrazinylC₁₋₄ alkyl, pyridazinylC₁₋₄ alkyl, tetrazolylC₁₋₄ alkyl,pyrrolidinylC₁₋₄ alkyl, morpholinylC₁₋₄ alkyl, imidazoliumC₁₋₄ alkyl,N-methylimidazoliumC₁₋₄ alkyl, pyridiniumC₁₋₄ alkyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, N-methylpyrimidinium, N-methylimidazolyl,pyridinium, pyrimidinium, tetrazolyl, phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or R¹ is of the formula --NR⁶ COR⁸ or--CH₂ NR⁶cor⁸ wherein R⁶ is hereinabove defined and R⁸ is hydroxy, pyridyloxy,pyrimidyloxy, pyrazinyloxy, pyridazinyloxy, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ alkylamino or optionally substitutedC₁₋₆ alkyl or R¹ is of the formula --CONR⁶ SO₂ R¹² or --CH₂ CONR⁶ SO₂R¹² wherein R⁶ is as hereinabove defined and R¹² is C₁₋₆ alkyl orphenyl, wherein alkyl groups and ring systems are optionallysubstituted.

Yet more preferably R¹ is carboxy, optionally substituted tetrazolyl,carboxymethyl, optionally substituted tetrazolylmethyl or of the formula--CONR⁶ R⁷ or of the formula --CH₂ CONR⁶ R⁷ wherein R⁶ is hydrogen ormethyl and R⁷ is hydrogen, C₁₋₆ alkoxycarbonyl, hydroxy, C₁₋₆ alkyl(optionally substituted by one or two substituents selected fromhydroxy, amino, C₁₋₄ alkoxy, halo, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylS(O)_(p) (p is 0, 1 or 2), cyano, carboxy, C₁₋₄ alkanoyl, C₁₋₄alkanoylamino, trifluoromethyl, pentafluoroethyl and nitro),cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, pyridylmethyl,pyrimidylmethyl, pyrazinylmethyl, pyrrolidinylmethyl, morpholinylmethyl,imidazoliumethyl or pyridiniummethyl, tetrazolylmethyl, pyridyl,N-methylpyrimidinyl, N-methylimidazolyl, tetrazolyl, phenyl (optionallysubstituted by hydroxy, nitro, halo, amino, methyl, ethyl, methoxy,ethoxy, cyano or trifluoromethyl), cyclopropyl, cyclobutyl, cyclohexylor hydroxycyclohexyl, or R¹ is of the formula --NR⁶ COR⁸ or --CH₂ NR⁶CCR⁸ wherein R⁶ is as hereinabove defined and R⁸ is hydroxy, pyridyloxy,C₁₋₆ alkoxy (wherein the alkyl group is optionally substituted byhydroxy, amino, halo, cyano, C₁₋₄ alkoxy, trifluoromethyl, C₁₋₄alkylS(O)_(p) -- (p is 0, 1 or 2), carboxy or C₁₋₄ alkoxycarbonyl), C₁₋₆alkylamino (wherein the alkyl group is optionally substituted byhydroxy, amino, halo, cyano, C₁₋₄ alkoxy, trifluoromethyl, C₁₋₄alkylS(O)_(p) -- (p is 0, 1 or 2), carboxy, C₁₋₄ alkoxycarbonyl orpyridyl) or C₁₋₄ alkyl (optionally substituted by hydroxy, halo,carboxy, C₁₋₄ alkoxycarbonyl, pyridyl or 2,4-dioxoimidazolidin-5-yl) orR¹ is of the formula --CONR⁶ SO₂ R¹² or --CH₂ CONR⁶ SO₂ R¹² wherein R⁶is as hereinabove defined and R¹² is C₁₋₄ alkyl or phenyl (wherein thealkyl and phenyl groups are optionally substituted by nitro, hydroxy,halo, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or trifluoromethyl).

Most preferably R¹ is carboxy, tetrazolyl,methanesulphonylaminocarbonyl, benzenesulphonylaminocarbonyl,(optionally substituted on the phenyl ring by nitro, hydroxy, halo,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano ot trifluoromethyl), or R¹ is ofthe formula --CONR⁶ R⁷ wherein R⁶ is hydrogen or methyl and R⁷ ispropyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-hydroxyethyl, tetrazolyl,tetrazolylmethyl, carboxymethyl, 1-carboxyethyl, 1-carboxypropyl or1-carboxy-3-hydroxypropyl.

Preferred optional substituents for ring carbon atoms in A, are halo,nitro, trifluoromethyl, cyano, amino, C₁₋₆ alkoxy, carbamoyl, C₁₋₄alkylcarbamoyl, di(C₁₋₄ alkyl)carbamoyl, C₁₋₄ alkanoylamino, C₁₋₄alkanesulphonamido, benzenesulphonamido, C₁₋₄ alkanoyl, C₁₋₄alkoxyiminoC₁₋₄ alkyl and hydroxyiminoC₁₋₄ alkyl, C₁₋₄ alkylS(C p-- ortrifluoromethylS(O)p-- (wherein p is 0, 1 or 2).

Preferably, when A is a 6-membered ring, it is unsubstituted orsubstituted in the 4-position relative to the --O--CH(R³)-- linkinggroup.

Preferred optional substituents for ring carbon atoms in B are hydroxy,halo, methoxy, cyano, trifluoromethyl, amino, N-methylamino orN,N-dimethylamino.

Preferred optional substituents for D are halo, nitro, hydroxy, cyano,methyl, amino, methoxy or carbamoyl.

Preferably A is unsubstituted or substituted by one substituent.

Preferably B is unsubstituted or substituted by one substituent.

Preferably D is unsubstituted.

Preferably Z is --(CH₂)₂ --, --(CH₂ ;₃ --, --CH═CH--, --CH═CHCH₂ --,--CH₂ CH═CH-- or --CH(Me)CH₂ CH₂ -- wherein the left side of the linkinggroup is attached to ring A and the right side to ring B.

Most preferably Z is --(CH₂)₂ --, --(CH₂)-- or --CH═CH--.

Preferably R³ is hydrogen.

A preferred class of compounds is that of the formula (III):

wherein ##STR9## R¹, R³, and Z are as hereinabove defined, R¹³ ishydrogen, halo, trifluoromethyl, nitro, hydroxy, amino, C₁₋₄ alkylamino,di C₁₋₆ alkyl!amino, cyano, C₁₋₆ alkoxy, carboxy, allyloxy, S(O)_(p)C₁₋₆ alkyl (p is 0, 1 or 2), S(O)_(p) -- phenyl (p is 0, 1 or 2), C₁₋₆alkyl (optionally substituted by hydroxy, C₁₋₄ alkoxy, amino, halo,nitro, S(O)_(p) C₁₋₄ alkyl (p is 0, 1 or 2), S(O)_(p) -phenyl (p is 0, 1or 2) or cyano), carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄alkyl)carbamoyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₃ alkyl, C₃₋₇ cycloalkylC₂₋₃ alkenyl, C₅₋₇ cycloalkenyl,C₅₋₇ cycloalkenylC₂₋₃ alkenyl, benzyl, benzoyl, benzyloxy, C₁₋₄alkoxycarbonylamino, C₁₋₄ alkanoylamino, (wherein the alkanoyl group isoptionally substituted by hydroxy), C₁₋₄ alkanoyl(N--C₁₋₄ alkyl)amino,wherein the alkanoyl group is optionally substituted by hydroxy), C₁₋₄alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C₁₋₄alkylaminosulphonyl, di(C₁₋₄ alkyl)aminosulphonyl, C₁₋₄ alkoxycarbonyl,C₂₋₄ alkanoyloxy, C₁₋₆ alkanoyl, formylC₁₋₄ alkyl, trifluoroC₁₋₃alkylsulphonyl, 1-(hydroxyimino)-1-(phenyl)methyl, 1-(C₁₋₄alkoxyimino)-1-(phenyl)methyl, hydroxyiminoC₁₋₆ alkyl, C₁₋₄alkoxyiminoC₁₋₆ alkyl, C₁₋₆ alkylcarbamoylamino, carboxyC₁₋₄ alkoxy,C₂₋₆ alkenyl (substituted by halo), N-(amino)iminoC₁₋₄ alkyl, N-(C₁₋₄alkylamino)iminoC₁₋₄ alkyl, N- di(C₁₋₄ alkyl)amino!iminoC₁₋₄ alkyl,N-(phenyl)aminoiminoC₁₋₄ alkyl, 5-membered heteroaryl containing 1 or 2heteroatoms selected from nitrogen, oxygen and sulphur, tetramethylene,and diradicals of the formula --(CH₂)₃ CO--, --(CH₂)₃ C(═--OH)-- and--(CH₂)₃ C(═N--OC₁₋₄ alkyl)-- and B is phenyl or hydroxypyridyl.

Particular compounds of the present invention are:

4- 3-(2-benzyloxy-5-fluorophenyl)butyl!benzoic acid;

4- 3-(2-(4-methoxybenzyloxy)phenyl)propyl!benzoic acid;

N-(4-nitrobenzenesulphonyl)-4-3-(2-benzyloxyphenyl)propyl!-benzenecarboxamide;

4- 3-(2-benzyloxy-5-fluorophenyl)propyl!benzoic acid;

5- 4-(2-benzyloxyphenethyl)phenyl!tetrazole;

4- 2-benzyloxyphenethyl)-3-fluorobenzoic acid;

5-(4-(2-(2-benzyloxyphenyl)ethenyl)phenyl!tetrazole;

4- 3-(2-benzyloxy-5-chlorophenyl)propyl!benzoic acid;

4- 3-(2-(3-chlorobenzyloxy)phenyl)propyl!benzoic acid;

4- 3-(2-benzyloxynaphth-1-yl)propyl!benzoic acid;

4- 3-(2-benzyloxy-5-acetylphenyl)propyl!benzoic acid;

4- 3-(2-benzyloxy-5-nitrophenyl)propyl!benzoic acid;

4- 2-benzyloxy-5-chlorophenethyl!benzoic acid;

5- 4-(5-acetyl-2-benzyloxyphenethyl)phenyl!tetrazole;

5- 4-(2-benzyloxy-5-bromophenethyl)phenyl!tetrazole;

5-6-(2-benzyloxy-5-bromophenethyl)-1-methyl-1,2-dihydro-2-oxopyridin-3-yl!tetrazole;

4- 3-(2-benzyloxy-5-(1-hydroxyiminoethyl)phenyl)propyl!benzoic acid;

4- 2-benzyloxyphenethyl!-2-hydroxybenzoic acid;

4- 3-(2-benzyloxyphenyl)propyl!-2-hydroxybenzoic acid;

4- 3-(2-benzyloxy-5-methylthiophenyl)propyl!benzoic acid;

2-2-benzyloxy-5-bromophenethyl!-3,4-dihydro-3-ethyl-4-oxopyrimidin-5-carboxylicacid;

4- 2- 2-benzyloxyphenyl!ethenyl!-3-bromobenzoic acid;

4- 2-(2-benzyloxyphenyl)ethenyl!-3-methoxybenzoic acid;

4- 3-(2-benzyloxy-5-(2-methylpropionyl)phenyl)propyl!benzoic acid;

5- 4-(2-benzyloxy-5-chlorophenethyl)phenyl!tetrazole;

4-(2-benzyloxy-5-bromophenethyl)-2-hydroxybenzoic acid;

4-(2-benzyloxyphenethyl)-3-bromobenzoic acid;

4- 3-(2-benzyloxy-5-(1-(phenyl)hydroxyiminomethyl)phenyl)propyl!-benzoicacid;

4-(2-benzyloxy-5-bromophenylethyl)-2-methoxybenzoic acid;

4- 3-(2-benzyloxy-5-fluorophenyl)propyl!benzoic acid;

N-benzenesulphenyl-4-3-(2-benzyloxy-5-chlorophenyl)propyl!-benzenecarboxamide;

4- 3-(2-benzyloxy-5-(1-(2-phenylhydrazino)ethyl)phenyl)propyl!benzoicacid;

4- 2-(2-benzyloxy-5-methylthiophenyl)ethenyl!-2-hydroxybenzoic acid;

5- 4-(2-benzyloxyphenethyl)-3-methoxyphenyl!tetrazole;

4- 3-(2-benzyloxyphenyl)propyl!-3-bromobenzoic acid;

5- 4-(2-benzyloxyphenethyl)-3-bromophenyl!tetrazole;

4- 3-(2-benzyloxyphenyl)propyl!-3-cyanobenzoic acid;

5- 4-(3-(2-benzyloxyphenyl)propyl)-3-bromophenyl!tetrazole;

4-(2-benzyloxy-5-methylthiophenethyl)-2-hydroxybenzoic acid;

5- 4-(3-(2-benzyloxyphenyl)propyl)-3-methoxyphenyl!tetrazole;

4- 2-benzyloxy-5-chlorophenethyl)-3-methoxy benzoic acid;

5- 4-(2-benzyloxy-5-chlorophenethyl)-3-methoxyphenyl!tetrazole;

4-(2-benzyloxy-5-methoxyphenethyl)-2-hydroxybenzoic acid; or

4-(2-benzyloxy-5-methylphenethyl)-2-hydroxybenzoic acid; or

a pharmaceutically acceptable salt thereof

It is to be understood that, insofar as certain of the compounds offormula (I) defined above may exist in optically active or racemicforms, by virtue of the compounds of the formula (I) containing anasymmetric carbon atom, the invention includes in its definition ofactive ingredient any such optically active or racemic form whichpossesses anti-hyperalgesic properties. The synthesis of opticallyactive forms ray be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,the pain relieving effects may be evaluated using the standardlaboratory techniques referred to hereinafter.

An in vivo hydrolysable ester or amide of a compound of the formula (I)containing carboxy group is, for example, a pharmaceutically acceptableester or amide which is hydrolysed in the human or animal body toproduce the parent acid, for example, a pharmaceutically acceptableester or amide formed with a (1-6C)alcohol such as methanol, ethanol,ethylene glycol, propranol or butanol, or with a phenol or benzylalcohol such as phenol or benzyl alcohol or a substituted phenol orbenzyl alcohol wherein the substituent is, for example, a halo (such asfluoro or chloro), (1-4C)alkyl (such as methyl) or (1-4C)alkoxy (such asmethoxy) group.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example an acid addition saltwith an inorganic or organic acid such as hydrochloric, hydrobromic,sulphuric, trifluoroacetic, citric or maleic acid; or, for example asalt of a tricyclic heterocycle of the invention which is sufficientlyacidic, for example an alkali or alkaline earth metal salt such as acalcium or magnesium salt, or an ammonium salt, or a salt with anorganic base such as methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

In a further aspect the invention provides a process for preparingcompounds of the formula (I) or pharmaceutically acceptable salts or invivo hydrolysable amides or ester thereof, which comprises deprotectinga compound of the formula (VI): ##STR10## wherein R²⁰ is R¹ or protectedR¹, R³, Z, n, A, B and D are as hereinabove defined, and any optionalsubstituents are optionally protected and at least one protecting groupis present; and thereafter if necessary:

i) forming a pharmaceutically acceptable salt;

ii) forming an in vivo hydrolysable ester or amide;

iii) converting one optional substituent into another optionalsubstituent.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question, and may beintroduced by conventional methods.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

A suitable protecting group for a hydroxy group is, for example, anarylmethyl group (especially benzyl), a tri-(1-4C)alkylsilyl group(especially trimethylsilyl or tert-butyldimethylsilyl), anaryldi-(1-4C)alkylsilyl group (especially dimethylphenylsilyl), adiaryl-(1-4C)alkylsilyl group (especially tert-butyldiphenylsilyl), a(1-4C)alkyl group (especially methyl), a (2-4C)alkenyl group (especiallyallyl), a (1-4C)alkoxymethyl group (especially methoxymethyl) or atetrahydropyranyl group (especially tetrahydroyran-2-yl). Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.Alternatively a trialkylsilyl or an aryldialkylsilyl group such as atert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed,for example, by treatment with a suitable acid such as hydrochloric,sulphuric, phosphoric or trifluoroacetic acid, or with an alkali metalor ammonium fluoride such as sodium fluoride or, preferably,tetrabutylammonium fluoride. Alternatively an alkyl group may beremoved, for example, by treatment with an alkali metal(1-4C)alkylsulphide such as sodium thioethoxide or, for example, bytreatment with an alkali metal diarylphosphide such as lithiumdiphenylphosphide or, for example, by treatment with a boron oraluminium trihalide such as boron tribromide. Alternatively a(1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric ortrifluoroacetic acid.

Alternatively a suitable protecting group for a hydroxy group is, forexample, an acyl group, for example a (2-4C)alkanoyl group (especiallyacetyl) or an aroyl group (especially benzoyl). The deprotectionconditions for the above protecting groups will necessarily vary withthe choice of protecting group. Thus, for example, an acyl group such asan alkanoyl or an aroyl group may be removed, for example, by hydrolysiswith a suitable base such as an alkali metal hydroxide, for examplelithium or sodium hydroxide.

A suitable protecting group for an amino, imino or alkylamino group is,for example, an acyl group, for example a (2-4C)alkanoyl group(especially acetyl), a (1-4C)alkoxycarbonyl group (especiallymethoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), anarylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroylgroup (especially benzoyl). The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.

Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl oraroyl group may be removed for example, by hydrolysis with a suitablebase such as an alkali metal hydroxide, for example lithium or sodiumhydroxide. Alternatively an acyl group such as a tert-butoxycarbonylgroup may be removed, for example, by treatment with a suitable acidsuch as hydrochloric, sulphuric or phosphoric acid or trifluoroaceticacid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl groupmay be removed, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a (1-4C)alkyl group (especially methyl orethyl) which may be removed, for example, by hydrolysis with a suitablebase such as an alkali metal hydroxide, for example lithium or sodiumhydroxide; or, for example, a tert-butyl group which may be removed, forexample, by treatment with a suitable acid such as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid.

In another aspect the compounds of the formula (I) or (VI) may beprepared:

a) converting R²² to R²⁰ in a compound of the formula (VII): ##STR11##wherein A, B, D, R³, Z, and n are as hereinabove defined and R²² is aprecursor of R²⁰ ;

b) when Z is --(CH(R⁵))_(m) -- by reducing a compound of the formula(VIII): ##STR12## wherein A, B, D, R³, R⁵, R²⁰, n, p and a are ashereinabove defined;

c) when Z is --(CHR⁵)_(t) C(═O) (CHR⁵)_(u) -- or (CH(R⁵))_(m) -- and mis 3 or 4, by reducing a compound of the formula (IX): ##STR13## whereinA, B, D, R³, R⁵, R²⁰, and n are as hereinabove defined and one of r ands is o and the other is 1;

d) when B is an activated heterocycle and Z is --(CH(R⁵))m--, byreacting a compound of the formula (X) with a compound of the formula(XI): ##STR14## wherein A, B, D, R³, R⁵, R²⁰, n and m are as hereinabovedefined and L is a leaving group;

e) when Z is --(CHR⁵)_(p) CR⁵ ═CR⁵ (CHR⁵)_(q) --, by reacting a compoundof the formula (XII) with a compound of the formula (XIII): ##STR15##wherein A, B, D, R³, R⁵, R²⁰, p, q and n are as hereinabove defined andR²³ -R²⁵ are independently C₁₋₆ alkyl or optionally substituted phenyl;

f) when Z is --(CHR⁵)_(t) CH═CH(CHR⁵) and t is 0 or 1, by dehydrating acompound of the formula (XIV): ##STR16## wherein A, B, D, R³, R⁵, R²⁰,and n are as hereinabove defined, and t is 0 or 1; or

g) by reacting a compound of the formula (XV) with a compound of theformula (XVI): ##STR17## wherein A, B, D, Z, R³, R²⁰, and n are ashereinabove defined and L¹ is a leaving group; or

h) by reacting a compound of the formula (XVII) with a compound of theformula (XVIII): ##STR18## wherein A, B, D, R³, R⁵, R²⁰, n, r and s areas hereinabove defined; and thereater if necessary:

i) removing any protecting groups;

ii) forming a pharmaceutically acceptable salt;

iii) forming an in vivo hydrolysable ester or amide;

iv) converting an optional substituent into another optionalsubstituent.

Particular values for R²² include cyano, carbamoyl, alkoxycarbonyl,carboxy and activated carboxy groups such as acid chlorides andactivated esters.

The cyano group may be converted into a tetrazole ring by reacting, forexample, with ammonium or tin azide in an aprotic solvent such as DMF,in a temperature range of 100° C. to 130° C. For further information ontetrazole synthesis see S. J. Wittenberger and B. J. Donner JOC, 1993,58, 4139-4141; B E Huff et al, Tet. Lett, 1993, 50, 8011-8014; and J. V.Duncia et al, JOC 1991, 56, 2395-2400.

Alkoxycarbonyl may be converted into a carboxy group by acid or basehydrolysis. For example, base hydrolysis may be carried out in anorganic solvent such as methanol or THF in a temperature range ofambient to 100° C., in the presence of sodium hydroxide or potassiumhydroxide.

Acid hydrolysis may, for example, be carried out or in neat formic acidor neat trifluoroacetic acid optionally in an organic solvent such asdichloromethane.

An alkoxycarbonyl or an activated carboxy group, such as an acidchloride or activated ester, or an acyl group such as an alkanoyl groupmay be converted to an amide group by reacting with the appropriateamine in an inert solvent such as DMF or dichloromethane, in atemperature range of 0° C. to 150° C., preferably around ambienttemperature, in the presence of a base such as triethylamine.

The compounds of the formula (VII) may be prepared using processes b),c), d), e), f) or g) from the appropriate starting materials wherein R⁷is replaced with R¹⁰.

The compounds of the formula (VIII) may be reduced under standardconditions known in the art for the reduction of olefins, for example,catalytic hydrogenation using Raney nickel, platinum metal or its oxide,rhodium, zinc oxide, palladium-on-charcoal or Wilkinson's catalystRhCl(Ph₃ P)₃ ! as the catalyst.

Catalyst hydrogenation is conveniently carried out in the temperaturerange 0° C. to 150° C., but preferably at ambient temperature atslightly above atmospheric pressure, unless the double bond is highlysubstituted in which case higher temperatures and pressure may berequired, or Wilkinson's catalyst in which case a temperature ofapproximately 50° C. and pressure of approximately 50 atmospheres arepreferable.

Compounds of the formula (VIII) can be prepared using process e) orprocess f) above.

Compounds of the formula (IX) are reduced by standard methods known inthe art for the reduction of α,β-unsaturated ketones, without affectingring B. For example, the double bond may be hydrogenated catalyticallyusing Wilkinson's catalyst and then the ketone group reduced, ifappropriate, by forming the tosyl hydrazone and reducing with sodiumborohydride.

The compounds of the formula (IX) are conveniently prepared by reactinga compound of the formula (XVII) with a compound of the formula (XVIII).Suitable reaction conditions are described below.

The reaction between the compounds of the formulae (X) and (XI) isconveniently performed under standard conditions known in the art.Suitable leaving groups include halo, for example, chloro, bromo oriodo, and tosylate and mesylate.

In general the reaction is performed in an inert solvent such as hexane,tetrahydrofuran or ethyl ether, in a temperature range of -100° C. toambient temperature, in the presence of a strong base such as butyllithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide(LDA) or lithium hexamethyldisilylamide, preferably in the presence of ahindered base such as LDA or lithium hexamethyl disilylamide. Forexample wherein the leaving group is bromo, in tetrahydrofuran in thepresence of LDA at 30° C.

The compounds of the formula (X) are conveniently prepared by reacting acompound of the formula (XVI) with a compound of the formula (XX):##STR19## wherein A and R⁵ are as hereinabove defined and P is a hydroxyprotecting group, and thereafter deprotecting the hydroxy group andconverting it to a leaving group (L). Conversion of the hydroxy group toa leaving group is performed by standard processes known in the art.

For example when the leaving group is bromo, reacting the hydroxy groupwith phosphorous tribromide.

The reaction between compounds of the formulae (XVI) and (XX) areconveniently carried out under standard conditions known in the art forsuch ether-forming reactions, for example as described for the reactionbetween compounds of the formulae (XV) and (XVI). ##STR20## wherein B,R⁵, R²⁰, R²³ -R²⁵, p and q are as hereinabove defined and L¹¹ is aleaving group.

The compounds of the formulae (XII) and (XIII) are conveniently reactedtogether under conditions known for the Wittig reaction. For example inan inert solvent such as hexane, tetrahydrofuran, or diethyl ether in atemperature range of -78° C. to ambient. Preferably R²³ -R²⁵ are all thesame. In particular R²³ -R²⁵ are all phenyl.

The compounds of the formula (XIII) are rarely isolatable and usuallyprepared in situ by deprotonating a compound of the formula (XXI)(scheme I). Deprotonazion is usually carried out in an inert solventsuch as tetrahydrofruan or diethyl ether, in a temperature range of -78°C. to ambient, in the presence of a strong base. Examples of strongbases are lithium hexamethyldisilylamide, CH₃ SOCH₂ ⁻ Na⁺ and butyllithium.

Compounds of the formula (XXI) may be prepared by reacting a compound ofthe formula (XXII) with a compound of the formula (XXIII) (scheme I).Suitable values for L¹¹ include halogen, such as chloro, bromo or iodo.Typically an inert solvent such as acetonitrile, diethyl ether,tetrahydrofuran or toluene is used and a temperature range of 50° C. or120° C. The compounds of the formula (XXII) may be known or preparedfrom another compound of the formula (XXII) or a compound of the formula(XXIV): ##STR21## wherein B, R⁵, R²⁰ and q are as hereinabove defined.For example the compound of the formula (XXIV) may be reduced to acompound of the formula (XXII) wherein L¹¹ is hydroxy. A compound of theformula (XXII), wherein L¹¹ is hydroxy, may then be converted to acompound of the formula (XXII) wherein L¹¹ is bromo by, for example,bromonating with N-bromosuccinimide.

Compounds of the formula (XII) are conveniently prepared by reactingtogether compounds of the formulae (XXX) and (XVI). The --C(═O)R⁵ groupmay be protected if necessary. Reaction conditions for ether-formingreactions are known in the art, for example, those described below forthe reaction between compounds of the formulae (XV) and (XVI).

Dehydration of compounds of the formula (XIV) is conveniently carriedout using standard methods known in the art, for example, at elevatedtemperatures in the presence of sulphuric acid, phosphoric acid oraluminium oxide. The compounds of the formula (XIV) can be prepared byreacting a compound of the formula (XI) with a compound of the formula(XXV): ##STR22## wherein A, R³, R⁵, R²¹ and n are as hereinabovedefined.

The reaction between compounds of the formulae (XI) and (XIV) isconveniently performed in the presence of a base such as butyl lithium,sec-butyl lithium, LDA or lithium hexamethyldisilylamide.

Compounds of the formula (XXV) are conveniently prepared by reactingtogether compounds of the formulae (XVI) and (XXVI) ##STR23## wherein A,R⁵ and t are as hereinabove defined.

The reaction between compounds of the formulae (XVI) and (XXVI), inwhich of course the --C(═O)R⁵ group may be protected, is carried outunder conditions known in the art for such ether-forming reactions, forexample as described for the reaction between compounds of the formulae(XV) and (XVI) below.

The ether-forming reaction between compounds of the formulae (XV) and(XVI) is typically performed in an inert solvent such as acetone or DMF,in a temperature range of ambient to 60° C., in the presence of a mildbase. Suitable values for L¹ include tosylate, mesylate, triflate andhalo, for example chloro or bromo. When L¹ is bromo, compounds of theformulae (XV) and (XVI) may, for example, be reacted together in DMF, atambient temperature in the presence of a base such as potassiumcarbonate. When L¹ is hydroxy, the Mitsunobu reaction may be used (O.Synthesis, 1981, 1). For example reacting in tetrahydrofuran or toluenein the presence of diethyl azodicarboxylate and triphenylphosphine.

The compounds of the formula (XV) and XVI; may alternatively be reactedtogether using a phase transfer system.

Compounds of the formula (XV) may he prepared using processes a), b),c), d), e) or f) from the appropriate staring materials. Appropriatestarting materials corresponding to compounds of the formulae (VII),(VIII), (IX), (X), (XII) and (XIV) have a hydroxy group (or protectedhydroxy group), in place of the --OCH(R³)--Ph--(R²¹)_(n) group.

The reaction between compounds of the formulae (XVII) and (XVIII) isconveniently carried out in the presence of a base, for example, lithiumhydroxide or potassium tert-butoxide in an organic solvent such as analcohol, for example, methanol.

The compounds of the formula (XVII) may be prepared by reacting acompound of the formula (XVI) with a compound of the formula (XIX):##STR24## wherein A and R⁵ are as hereinabove defined. The reaction isconveniently carried out under standard conditions known in the art forsuch ether-forming reactions, for example, as described for the reactionbetween compounds of the formulae (XV) and (XVI).

The compounds of the formulae (XI), (XI), (XVIII), (XIX), (XX), (XXII),(XXIV), (XXVI) and (XXX) and starting materials for compounds of theformula (XV) are generally known in the art or can be made by methodsanalogous to or similar to those used in the examples or those known inthe art for related compounds.

It is also possible to synthesise certain intermediates and evenprotected compounds using primarly ring synthesis. Here, reference ismade to the compendiums `The Chemistry of Heterocyclic Compounds` E. C.Taylor and A. Weissberger (published by John Wiley and Sons) and`Comprehensive Heterocyclic Chemistry`, A. R Katritzky and C. W Rees(published by Pergamon Press (Elsevier)).

Optional substituents may be converted into other optional substituents.For example an alkylthio group may be oxidised to an alkylsulphinyl oralkylsulphonyl group, a nitro group reduced to an amino group, a hydroxygroup alkylated to a methoxy group, or a bromo group converted to analkylthio group.

Various substituents may be introduced into compounds of the formulae(I) and (III) and intermediates in the preparation of compounds of theformulae (I) and (III), when appropriate, using standard methods knownin the art. For example, an acyl group or alkyl group may be introducedinto an activated benzene ring using Friedel-Crafts reactions, a formylgroup by formylation with titanium tetrachloride and dichloromethylethyl ether, a nitro group by nitration with concentrated nitric acidconcentrated sulphuirc acid and bromination with bromine ortetra(n-butyl)ammonium tribromide.

It will be appreciated that, in certain steps in the reaction sequenceto compounds of the formula (I), it will be necessary to protect certainfunctional groups in intermediates in order to prevent side reactions.Deprotection may be carried out at a convenient stage in the reactionsequence once protection is no longer required.

As stated hereinbefore compounds of the formula (I) are antagonists ofthe pain enhancing effects of E-type prostaglandins and of value in therelief of mild to moderate pain which, for example, accompaniesinflammatory conditions such as rheumatoid arthritis and osteoarthritis.Certain properties of the compounds may be demonstrated using the testprocedures set out below:--

(a) an in-vitro guinea pig ileum assay which assesses the inhibitoryproperties of a test compound against PGE₂ -induced contractions of theileum; ileum was immersed in oxygenated Krebs solution containingindomethacin (4 μg/ml) and atropine (1 μM) and which was maintained at37° C.; the ileum was subject to a tension of 1 g; a control doseresponse curve for PGE₂ -induced contraction of the ileum was obtained;test compound (dissolved in dimethylsulphoxide) was added to the Krebssolution and a dose response curve for the PGE₂ -induced contraction ofthe ileum in the presence of the test compound was obtained; the pA₂value for the test compound was calculated;

(b) an in-vivo assay in mice which assesses the inhibitory properties ofa test compound against abdominal constriction response induced by theintraperitoneal administration of a noxious agent such as dilute aceticacid or phenylbenzoquinone (hereinafter PBQ) using the proceduredisclosed in European Patent Application No. 0218077.

Although the pharmacological properties of the compounds of the formulaI vary with structural change as expected, in general activity possessedby compounds of the formula I may be demonstrated at the followingconcentrations or doses in one or more of the above-mentioned Tests (a)and (b):--

Test (a):- pA₂ >5.3;

Test (b):- ED₃₀ in the range, for example, 0.01-100 mg/kg orally.

No overt toxicity or other untoward effects were noted in Test (b) whencompounds of the formula I are administered at several multiples oftheir minimum inhibitory dose.

Prostaglandin receptors and in particular receptors for PGE₂ have beententatively characterised by Kennedy et al. (Advances in Prostaglandin,Thromboxane and Leukotriene Research, 1983, 11, 327). The known PGE₂antagonist SC-19220 blocks the effect of PGE₂ on some tissues such asguinea pig ileum or dog fundus but not on other tissues such as the cattrachea or chick ileum. Those tissues which did possess SC-19220sensitive mediated effects were said to possess EP₁ receptors. Based onthis compounds of the present invention, possessing activity in Test(a), are EP₁ antagonists.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a compound of the formula (I)or an in-vivo hydrolysable ester thereof or an amide thereof, or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel, spray or aqueous oroily solution or suspension; for nasal use, for example a snuff, nasalspray or nasal drops; for vaginal or rectal use, for example asuppository or rectal spray; for administration by inhalation, forexample as a finely divided powder or a liquid aerosol; for sub-lingualor buccal use, for example a tablet or capsule; or for parenteral use(including intravenous, subcutaneous, intramuscular, intravascular orinfusion), for example a sterile aqueous or oily solution or suspension.In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The amount of active ingredient (that is a compound of the formula (I)or a pharmaceutically-acceptable salt thereof) that is combined with oneor more excipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

According to a further feature of the invention there is provided acompound of the formula (1) or an in-vivo hydrolysable ester or amide ora pharmaceutically-acceptable salt thereof, for use in a method oftreatment of the animal (including human) body by therapy.

According to a further feature of the invention there is provided theuse of a compound of the formula I, or an in-vivo hydrolysable ester oramide or a pharmaceutically-acceptable salt thereof, in the manufactureof a medicament for use in the relief of pain in the animal (includinghuman) body.

According to a further feature of the invention there is provided amethod for the relief of pain in the animal (including human) body inneed of such treatment which comprises administering to said body aneffective amount of a compound of the formula I, or an in-vivohydrolysable ester or amide or a pharmaceutically-acceptable saltthereof.

As mentioned above, a compound of the formula (I) is useful in treatingthe pain which, for example, accompanies inflammatory conditions such asrheumatoid arthritis and osteoarthritis. In using a compound of theformula I for therapeutic or prophylactic purposes it will generally beadministered so that a daily dose in the range, for example, 0.1 mg to75 mg per kg body weight is received, given if required in divideddoses. In general lower doses will be administered when a parenteralroute is employed. Thus, for example, for intravenous administration, adose in the range, for example, 0.05 mg to 30 mg per kg body weight willgenerally be used. Similarly, for administration by inhalation, a dosein the range, for example, 0.05 mg to 25 mg per kg body weight will beused.

Although the compounds of the formula (I) are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to antagonise the effects ofPGE₂ at the EP₁ receptor, based on test a). Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

By virtue of their ability to relieve pain, the compounds of the formulaI are of value in the treatment of certain inflammatory annon-inflammatory conditions which are currently treated with acyclooxygenase-inhibitory non-steroidal anti- inflammatory drug (NSAID)such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen,sulindac, tolmetin and piroxicam or other analgesics such asparacetamol, tramadol, Codein or in some circumstances morphine.Co-administration of a compound of the formula I with a NSAID can resultin a reduction of the quantity of the latter agent needed to produce atherapeutic effect. Thereby the likelihood of adverse side-effects fromthe NSAID such as gastrointestinal effects are reduced. Thus accordingto a further feature of the invention there as provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or an in-vivohydrolysable ester or amide or pharmaceutically-acceptable salt thereof,in conjunction or admixture with a cyclooxygenase inhibitorynon-steroidal anti-inflammatory agent, and a pharmaceutically-acceptablediluent or carrier.

The compounds of the invention may also be used with otheranti-inflammatory agents such as an inhibitor of the enzyme5-lipoxygenase (such as those disclosed in European Patent ApplicationsNos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662,0385663, 0385679, 0385680).

The compounds of the formula (I) may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compositions of the invention may in addition contain one or moreother therapeutic or prophylactic agents known to be of value for thetreatment of pain. Thus for example, a known opiate pain-killer (such asdextropropoxyphene, dehydrocodeine or codeine) or an antagonist of otherpain or inflammation mediators, such as bradykinin, neurokinin andcalcitonin gene related peptides (CGRP), or an alpha₂ -adrenoceptoragonist, a GABA_(B) receptor agonist, a calcium channel blocker, asodium channel blocker, a CCK_(B) receptor antagonist, or an antagonistor modulator of the action of glutamate at the NMDA receptor mayusefully also be present in a pharmaceutical composition of theinvention.

The compounds of the present invention may also be administered in bonediseases such as osteoporosis alone or in combination with calcitoninand bisphosphonates and estrogens.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:--

(i) evaporations were carried out by rotary evaporations in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) yields are given for illustration only and are not necessarily themaximum attainable;

(iii) the end-products of the formula I have satisfactory microanalysisand their structures were generally confirmed by NMR and mass spectraltechniques;

(iv) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(v) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were determined afterrecrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture;

(vi) the following abbreviations have been used:

DMF N,N-dimethylformamide;

THF tetrahydrofuran;

DMSO dimethylsulphoxide;

DIBAL diisobutylaluminium hydride;

DEAD diethylazodicarboxylate.

EXAMPLE 1

4- 3-(2-Benzyloxyphenyl)propyl)benzoic acid

(A) To a solution of methyl 4- 3-(2-benzyloxyphenyl)-propyl!benzoate(0.7 g) in ethanol was added 2M sodium hydroxide (1.45 ml). The mixturewas stirred for 18 hours, evaporated to dryness and mixed with 1M HCl(50 ml) and ethyl acetate (50 ml). The solutions were separated and theorganic solution washed with brine (50 ml), dried (magnesium sulphate),filtered and evaporated. The residue was purified by chromatography onsilica gel using ethyl acetate: hexane (1:1) as eluant. There was thusobtained 4- 3-(2-benzyloxyphenyl)propyl!benzoic acid (391 mg) m.p.109°-111° C.

The methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate was obtained asfollows:

(B) A mixture of 2-hydroxyacetophenone (79 g), benzyl bromide (99.3 g)and potassium carbonate (80 g) in acetone (250 ml) was heated at refluxfor 24 hours, filtered and the solvent evaporated. The residue wasdistilled (bp 138°-140 ° C., 0.05 mmHg and there was thus obtained2-benzyloxyacetophenone (124 g).

(C) A mixture of methyl 4-formylbenzoate (36.28 g),2-benzyloxyacetophenone (50 g) and potassium t-butoxide (2 g) inmethanol (150 ml) was stirred for 3 hours. The precipitate that formedwas filtered off. On standing further solid precipitated from thefiltrates and was filtered off and combined with the first solid. Therewas thus obtained methyl 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!benzoate (74.2 g).

(D) A mixture of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!benzoate (35 g), 10%Pd-carbon (7 g), acetic acid (350 mil) and trifluoroacetic acid (7 ml)was warmed at 30° C. under 10 atm. of hydrogen for 18 hours, filteredand the filtrates evaporated. The residue was triturated with hexane anddried to give methyl 4-(3-(2-hydroxyphenyl)propyl!benzoate (26 g).

(E) First alternative method to synthesise methyl 4-3-(2-hydroxyphenyl)propyl!benzoate. A mixture of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!benzoate (25 g) and 11%Pd-carbon (2.5 g) in ethyl acetate (300 ml) was stirred under atmosphereof hydrogen for 18 hours, filtered and the solvent evaporated. There wasthus obtained methyl 4-(3-(2-hydroxyphenyl)-3-carbonylpropyl!benzoate(21 g).

(F) To a stirred suspension of zinc powder (21 g) in water (50 ml) wasadded mercuric dichloride (1.5 g). After 20 minutes concentrated HCl (25ml) was added and the mixture stirred for 2 minutes, the aqueoussolution decanted off and a solution of methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl!benzoate (21 g) in methanol (100ml) added followed by concentrated HCI (50 ml). The mixture was heatedat reflux for 3 hours, cooled and the supernatant decanted off. The zincresidues were washed with diethyl ether (3×50 ml) and the combinedorganic washings and the supernatant were washed with water (100 ml),dried (magnesium sulphate), filtered and evaporated. The resulting oilwas triturated with hexane to give methyl 4-3-(2-hydroxyphenyl)propyl!benzoate (15.3 g) as a white solid.

(G) Second alternative method to synthesise methyl 4-3-(2-hydroxyphenyl)propyl!benzoate. To a mixture of2-(4-carboxyphenyl)-ethyltriphenylphosphonium bromide (prepared in thestandard way from 4-(2-bromoethyl)benzoic acid and triphenylphosphine)(9.4 g) in THF (70 ml) was added lithium hexamethyldisilazide (40 ml,1.0M solution in THF). After 1 hour a solution of2-benzyloxybenzaldehyde (commercially available, or prepared fromsalicylaldehyde and benzyl bromide using the method described below tosynthesise 4- 3-(2-hydroxyphenyl)propyl!benzoate) (4.0 g) in THF (40 ml)was added and the mixture stirred for 2 hours and poured into water (100ml) and diethyl ether (100 ml). The aqueous layer was separated andwashed with ethyl acetate (3×50 ml), acidified with 1 M HCl to pH1, andextracted with ethyl acetate (2×50 ml). The combined ethyl acetateextracts were washed with water 50 ml), dried (magnesium sulphate),filtered and evaporated to an orange oil (6 g).

(H) To a solution of the oil in methanol (100 ml) was added thionylchloride (1.3 ml) at 0° C. The mixture was stirred for 2 hours,evaporated and the residue dissolved in ethyl acetate (100 ml), washedwith sodium bicarbonate solution (50 ml) and brine (50 ml), the organiclayer separated, dried (magnesium sulphate), filtered and evaporated.The resulting residue was purified by chromatography on silica gel usingethyl acetate: hexane (2:3) as eluant. There was thus obtained a strawcoloured oil (4.2 g). 1.5 g of this material was converted to methyl 4-3-(2-hydroxyphenyl)propyl!benzoate using the hydrogenation methoddescribed above (for the conversion of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl)benzoate to methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl!benzoate using ethanol as thereaction solvent). There was thus obtained methyl 4-3-(2-hydroxy-phenyl)propyl! benzoate (1.1 g) as a white solid afterpurification by subjecting to chromatography on silica gel using ethylacetate as eluant.

(I) To a solution of 4- 3-(2-hydroxyphenyl)propyl!benzoate (1.0 g) inDMF (20 ml) was added potassium carbonate (0.76 g) and benzyl bromide(0.66 ml). The mixture was stirred for 18 hours, poured into water (100ml) and ethyl acetate (100 ml). The ethyl acetate solution was washedwith water (3×100 ml), dried (magnesium sulphate), filtered andevaporated. The residue was purified by subjecting to chromatography onsilica gel using diethyl ether: hexane (1:9) as eluant. There was thusobtained methyl 4- 3-(2-benzyloxy-phenyl)propyl!benzoate (0.7 g) as anoil.

EXAMPLE 2

The process described in Example 1 was repeated with the appropriatemethyl 4-(3-(2-benzyloxyphenyl)propyl)benzoates to give the compoundsdescribed in the following table with appropriate modificationsdescribed in the notes below. The methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate precursors were prepared frommethyl 4-(3-(2-hydroxyphenyl)propyl!benzoate and the appropriate benzylhalide using the method described in Example 1 for the preparation ofmethyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate.

    ______________________________________                                         ##STR25##                                                                    Compd No  R'          m.p.        Footnote                                    ______________________________________                                         1        4-F         79-80                                                    2        4-OMe       128-129                                                  3        4-NO.sub.2  168-170                                                  4        4-Me        119-120                                                  5        2-Me        131-132                                                  6        3-Cl        109-110                                                  7        2-Cl        110.5-111                                                8        4-Cl        126.5-127.5                                              9        3-NH.sub.2  125.5-126   a                                           10        3-NHCOMe    198-198.5   b                                           11        3-OAllyl    76.5-77.5   c                                           12        4-OAllyl    92.5-93.5   d                                           13        3-OH        103.5-104   c,e                                         14        2-OAllyl    126-126.5   f                                           ______________________________________                                        a:- Methyl 4- 3-(2-(3-aminophenylmethyloxy)phenyl)propyl!-benzoate            was prepared from methyl 4- 3-(2-(3-nitrophenylmethyloxy)-phenyl)             propyl!benzoate (prepared from methyl 4- 3-(2-hydroxyphenyl)-propyl!          benzoate and 3-nitrobenzyl chloride) as follows:                              A mixture of methyl 4- 3-(2-(3-nitrophenylmethyloxy)-phenyl)propyl!           benzoate (0.25 g), tin (II) chloride dihydrate (0.7 g) in ethanol (10         ml)                                                                           was heated at 70° C. for 45 minutes, cooled and poured onto ice.       The                                                                           pH of the solution was adjusted to 8 with sodium bicarbonate and ex-          tracted with ethyl acetate (2 × 50 ml). The combined organics were      washed with brine (50 ml), dried (magnesium sulphate), filtered and           evaporated. The residue was purified by subjecting to chromatography          on silica gel using ethyl acetate: hexane (1:9) as eluant. There was          thus obtained methyl 4- 3-(2-(3-aminophenylmethyloxy)phenyl)propyl!           benzoate (185 mg).                                                            b:- Methyl 4- 3-(2-(3-methylcarbonylaminophenylmethyloxy)-phenyl)             propyl!benzoate was prepared from methyl 4- 3-(2-(3-amino-                    phenylmethyloxy)phenyl)propyl!benzoate (preparation described in note         a) as follows:                                                                To a mixture of methyl 4- 3-(2-(3-aminophenylmethyloxy)-phenyl)propyl!        benzoate (0.2 g), triethylamine (0.19 ml) in dichloromethane (10 ml) at       5° C. was added acetic anhydride (0.08 ml). The mixture was            stirred                                                                       for 18 hours, the solvent evaporated, the residue dissolved in ethyl          acetate (50 ml), and washed with 1M HCl (50 ml), sodium bicarbonate           solution (50 ml) and brine (50 ml), dried (magnesium sulphate), filtered      and evaporated. There was thus obtained methyl 4- 3-(2-(3-methyl-             carbonylaminophenyl-methyloxy)-phenyl)propyl!benzoate (173 mg).               c:- (A) 3-Allyloxybenzyl chloride was obtained as follows:                    A mixture of 3-hydroxybenzaldehyde (6 g), allyl bromide (6.25 g), and         potassium carbonate (8.82 g) in DMF (30 ml) was stirred for 18 hours,         poured into water (100 ml) and extracted with diethyl ether                   (3 × 150 ml). The combined organic extracts were washed with water      (2 × 150 ml) and brine (2 × 150 ml), dried (magnesium             sulphate)                                                                     filtered and evaporated to give 2-allyloxybenzaldehyde (7.2 g).               (B) To a solution of 3-allyloxybenzaldehyde (7.2 g) in methanol (50 ml)       at 0° C. was added sodium borohydride (1 g) in portions. The           mixture was stirred for 30 minutes, evaporated, dissolved in 5% acetic        acid and extracted with diethyl ether (3 × 100 ml), washed with         water (2 × 100 ml), and sodium bicarbonate (2 × 100 ml),          dried (magnesium sulphate), filtered and evaporated to give 3-allyl-          oxybenzyl alcohol (7.26 g).                                                   (C) To a solution of 3-allyloxybenzyl alcohol (7.2 g) in dichloromethane      (100 ml) at 0° C. was added thionyl chloride (4.8 ml) in               dichloro-                                                                     methane dropwise and a drop of DMF and the mixture stirred at ambient         temperature for 1.5 hours, and poured into cold sodium bicarbonate            solution. The organic layer was washed with sodium bicarbonate                (2 × 100 ml), dried (magnesium sulphate), filtered and evaporated       to give 3-allyloxybenzyl chloride (8.3 g).                                    d:- 4-Allyloxybenzyl chloride was made from 4-hydroxy-benzaldehyde            using the methods in note c.                                                  e:- Methyl 4- 3-(2-(3-hydroxyphenylmethyloxy)phenyl)propyl!-                  benzoate was obtained from methyl 4- 3-(2-(3-allyloxyphenylmethyl-            oxy)phenyl)propyl!benzoate as follows:                                        To a solution of methyl 4- 3-(2-(3-allyloxy-phenylmethyloxy)phenyl)           propyl!benzoate (0.66 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione               (0.46 g) in DMF (12 ml) was added palladium tetrakistriphenylphosphine        (0.11 g) in DMF (12 ml) and the mixture was stirred for 18 hours in           the dark with argon bubbling through the solution. The mixture was            poured into ethyl acetate (100 ml) washed with water (2 × 100 ml),      and sodium bicarbonate (2 × 100 ml), dried (magnesium sulphate),        filtered and evaporated. The residue was purified by subjecting to            chromatography on silica gel using ethyl acetate: hexane (1:9, 2:8)           as eluant. There was thus obtained methyl 4- 3-(2-(3-hydroxyphenyl-           methyloxy)phenyl)propyl!benzoate (440 mg).                                    f:- 2-Allyloxybenzyl chloride was made from 2-hydroxy-benzaldehyde            using the methods in note c.                                              

a: Methyl 4- 3-(2-(3-aminophenylmethyloxy)phenyl)propyl!-benzoate wasprepared from methyl 4- 3-(2-(3-nitrophenylmethyloxy)-phenyl)propyl!benzoate (prepared from methyl 4- 3-(2-hydroxyphenyl)-propyl!benzoateand 3-nitrobenzyl chloride) as follows:

A mixture of methyl 4-3-(2-(3-nitrophenylmethyloxy)-phenyl)propyl!benzoate (0.25 g), tin (II)chloride dihydrate (0.7 g) in ethanol (10 ml) was heated at 70° C. for45 minutes, cooled and poured onto ice. The pH of the solution wasadjusted to 8 with sodium bicarbonate and extracted with ethyl acetate(2×50 ml). The combined organics were washed with brine (50 ml), dried(magnesium sulphate), filtered and evaporated. The residue was purifiedby subjecting to chromatography on silica gel using ethyl acetate hexane(1:9) as eluant. There was thus obtained methyl 4-3-(2-(3-aminophenylmethyloxy)phenyl)propyl!benzoate (185 mg). b: -Methyl 4- 3-(2-(3-methylcarbonylaminophenylmethyloxy)-phenyl)propyl!benzoate was prepared from methyl 4-3-(2-(3-amino-phenylmethyloxy)phenyl)propyl!benzoate (preparationdescribed in note a) as follows:

To a mixture of methyl 4-3-(2-(3-aminophenylmethyloxy)-phenyl)propyl!benzoate (0.2 g),triethylamine (0.19 ml) in dichloromethane (10 ml) at 5° C. was addedacetic anhydride (0.08 ml). The mixture was stirred for 18 hours, thesolvent evaporated, the residue dissolved in ethyl acetate (50 ml), andwashed with 1M HCl (50 ml), sodium bicarbonate solution (50 ml) andbrine (50 ml), dried (magnesium sulphate), filtered and evaporated.There was thus obtained methyl 4-3-(2-(3-methylcarbonylaminophenyl-methyloxy)-phenyl)propyl!benzoate (173mg).

c:- (A) 3-Allyloxybenzyl chloride was obtained as follows: A mixture of3-hydroxybenzaldehyde (6 g), allyl bromide (6.25 g), and potassiumcarbonate (8.82 g) in DENT (30 ml) was stirred for 18 hours, poured intowater (100 ml) and extracted with diethyl ether (3×150 ml). The combinedorganic extracts were washed with water (2×150 ml) and brine (2×150 ml),dried (magnesium sulphate) filtered and evaporated to give2-allyloxybenzaldehyde (7.2 g).

(B) To a solution of 3-allyloxybenzaldehyde (7.2 g) in methanol (50 ml)at 0° C. was added sodium borohydride (1 g) in portions. The mixture wasstirred for 30 minutes, evaporated dissolved in 5% acetic acid andextracted with diethyl ether (3×100 ml) , washed with water (2×100 ml),and sodium bicarbonate (2×100 ml), dried (magnesium sulphate), filteredand evaporated to give 3-allyloxybenzyl alcohol (7.26 g).

(C) To a solution of 3-allyloxybenzyl alcohol (7.2 g) in dichloromethane(100 ml) at 0° C. was added thionyl chloride (4.8 ml) in dichloromethanedropwise and a drop of DMF and the mixture stirred at ambienttemperature for 1.5 hours, and poured into cold sodium bicarbonatesolution. The organic layer was washed with sodium bicarbonate (2×100ml), dried (magnesium sulphate), filtered and evaporated to give3-allyloxybenzyl chloride (8.3 g).

d:- 4-Allyloxybenzyl chloride was made from 4-hydroxy-benzaldehyde usingthe methods in note c.

e:- Methyl 4- 3-(2-(3-hydroxyphenylmethyloxy)phenyl)propyl!-benzoate wasobtained from methyl 4-3-(2-(3-allyloxyphenylmethyl-oxy)phenyl)propyl!benzoate as follows:

To a solution of methyl 4-3-(2-(3-allyloxy-phenylmethyloxy)phenyl)propyl!benzoate (0.66 g) and2,2-dimethyl-1,3-dioxane-4,6-dione (0.46 g) in DMF (12 ml) was addedpalladium tetrakistriphenylphosphine (0.11 g) in DMF (12 ml) and themixture was stirred for 18 hours in the dark with argon bubbling throughthe solution. The mixture was poured into ethyl acetate (100 ml) washedwith water (2×100 ml), and sodium bicarbonate (2×100 ml), dried(magnesium sulphate), filtered and evaporated. The residue was purifiedby subjecting to chromatography on silica gel using ethyl acetate:hexane(1:9, 2:8) as eluant. There was thus obtained methyl 4-3-(2-(3-hydroxyphenylmethyloxy)phenyl)propyl!benzoate (440 mg).

f:- 2-Allyloxybenzyl chloride was made from 2-hydroxy-benzaldehyde usingthe methods in note c.

EXAMPLE 3

(A) The process described in Example 1 was repeated with the appropriatemethyl 4- 3-(2-benzyloxyphenyl)alkyllbenzoates or 4-3-(2-benzyloxyphenyl)alkyl)phenylethanoates to give the compoundsdescribed in the following table with appropriate modificationsdescribed in the notes below.

(B) The substituted methyl 4- 2-hydroxyphenylalkyl!-benzoate and4-(2-hydroxyphenylalkyllphenylethanoate compounds were obtained from thecorresponding 2-benzyloxybenzaldehyde using a similar method to that ofexample 1 (B) or benzyloxyphenylacetaldehydes obtained from thecorresponding 2-hydroxybenzaldehydes and phosphonium salts using thesecond alternative method to synthesise methyl 4-3-(2-hydroxyphenyl)propyl!-benzoate described in Example 1 unless statedotherwise in the notes.

(C) The methyl 4- 3-(2-benzyloxyphenyl)alkyl!benzoate precursors wereprepared from the substituted methyl 4-(2-hydroxyphenyl)-alkyl!benzoateor 4-(2-hydroxyphenyl)alkyl!phenylethanoate compounds and benzyl bromideusing the method describe example 1 for the preparation of methyl 4-3-(2-benzyloxyphenyl-propyl!benzoate unless stated otherwise in thenotes.

    __________________________________________________________________________     ##STR26##                                                                    Compd                                  Foot-                                  No. R1           Link   R2       m.p.  note                                   __________________________________________________________________________     1  H            CH.sub.2 CH.sub.2                                                                    CO.sub.2 H                                                                             143-144                                                                             a                                       2  H            CH.sub.2 CH.sub.2                                                                    CH.sub.2 CO.sub.2 H                                                                    88-89 b                                       3  5-Cl         CH.sub.2 CH.sub.2                                                                    CH.sub.2 CO.sub.2 H                                                                    91-92 b                                       4  5-F          CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             102-103                                       5  5-Cl         CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             95.5-96.5                                     6  5-OMe        CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             102-103                                       7  6-OMe        CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             90-91                                         8  4-OMe        CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                               121-121.5                                   9  6-F          CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             92-93                                        10  3,5-diCl     CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                               163-163.5                                  11  5-NO.sub.2   CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             161-163                                                                             c                                      12  5-NH.sub.2   CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             152-155                                                                             d                                      13  5-NHCOMe     CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             181-183                                                                             e                                      14  5-NHCO.sub.2 Et                                                                            CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             165-167                                                                             f                                      15  5-NHSO.sub.2 Ph                                                                            CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             159-161                                                                             g                                      16  5-NHMe       CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             153-154                                                                             h                                      17  5-NEt.sub.2  CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             67-68 i                                      18  5-COMe       CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                               147-147.5                                                                         j                                      19  5-CO-nPentyl CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                               136-136.5                                                                         k                                      20  5-n-Hexyl    CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             91.5-92                                                                             l                                      21  5-Br         CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             115-118                                                                             m                                      22  5-CN         CH2CH2CH2                                                                            CO.sub.2 H                                                                             134-135                                                                             n                                      23  5-CHO        CH.sub.2 CH.sub.2 CH                                                                 CO.sub.2 H                                                                             126-127                                                                             o                                      24  5-CH.sub.2 OH                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             102-103                                                                             p                                      25  5-C(NOH)Me   CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             166.5-167.5                                                                         q                                      26  5-C(NOH)H    CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             143.5-144                                                                           r                                      27  5-C(NOMe)Me  CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             121-122                                                                             s                                      28  5-Cl         CH.sub.2 CH.sub.2                                                                    CO.sub.2 H                                                                             145-147                                                                             a                                      29  5-NO.sub.2   CH.sub.2 CH.sub.2                                                                    CO.sub.2 H                                                                             183-184                                                                             a,t                                    30  5-SOMe       CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             101-102                                                                             u                                      31  5-SO.sub.2 Me                                                                              CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             185   v                                      32  H            CH.sub.2 CH.sub.2 CH.sub.2                                                           CONHCH.sub.2 CO.sub.2 H                                                                101-102                                                                             w                                      33  H            CH.sub.2 CH.sub.2 CH.sub.2                                                           CONH(CH.sub.2).sub.2 CO.sub.2                                                          115-116                                                                             x                                      34  5,6-CHCHCHCH CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             128-130                                      35  5,6-(CH.sub.2).sub.4                                                                       CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             138-139                                                                             y                                      36  3-NO.sub.2   CH.sub.2 CH.sub.2 CH.sub.2                                                           CO.sub.2 H                                                                             117-119                                      37  5-C(O)CHMe.sub.2                                                                           (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             135-137                                                                             z                                      38  5-C(NOH)CHMe.sub.2                                                                         (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             170-176                                                                             (aa)                                   39  5-COEt       (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             116-118                                                                             (ab)                                   40  5-COPh       (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             142-144                                                                             (ac)                                   41  5-C(NOH)Et   (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             168-170                                                                             (aa)                                   42  5-C(NOH)Ph   (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             180-189                                                                             (aa)                                   43  5-C(NNHCONH.sub.2)CH.sub.3                                                                 (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             158-160                                                                             (ad)                                   44  5-C(NHNH.sub.2)CH.sub.3                                                                    (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             174-180                                                                             (ae)                                   45  5-C(NHNHPh)CH.sub.3                                                                        (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             143-147                                                                             (af)                                   46  5-CH.sub.2 OMe                                                                             (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             81-84 (ag)                                   47  5-CH.sub.2 SMe                                                                             (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             107.5-111                                                                           (ah)                                   48  5-CH.sub.2 SO.sub.2 Me                                                                     (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             159.5-164                                                                           (ai)                                   49  5-CH.sub.2 SOMe                                                                            (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             137.5-140.5                                                                         (ai)                                   50                                                                                 ##STR27##   (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             177.5-181.5                                                                         (aj)                                   51  5-NEt.sub.2  (CH.sub.2).sub.3                                                                     CO.sub.2 H                                                                             67-68 (ak)                                   52  5-Br         (CH.sub.2).sub.2                                                                     CO.sub.2 H                                                                             166-167                                                                             (al)                                   __________________________________________________________________________    a:                                                                              (4-Carboxyphenylmethyl)triphenylphosphonium bromide was prepared in the       standard way                                                                  from 4-(bromomethyl)benzoic acid and triphenylphosphine.                    b:                                                                              (4-Carboxymethylphenylmethyl)triphenylphosphonium bromide was prepared        in the standard                                                               way from 4-(bromomethyl)phenylacetic acid and triphenylphosphine.           c:                                                                              Methyl 4- 3-(2-hydroxy-5-nitrophenyl)propyl!benzoate was prepared from        methyl                                                                        4- 3-(2-hydroxyphenyl)propyl!benzoate (see Example 1) as follows:             Nitric acid (15M, 3.13 ml) was added to acetic anhydride (12.52 ml) a         0° C. and the mixture                                                  stirred for 15 minutes, then added to a stirred solution of methyl            4- 3-(2-hydroxy-                                                              phenyl)propyl!benzoate (12.89 g) in acetic anhydride (300 ml) at              0° C. and stirred for 18                                               hours. The solvent was evaporated and the resulting yellow oil purified       by chromatography on                                                          silica gel using ethyl acetate:hexane (1:9 to 1:1 gradient) as eluant         to give methyl 4- 3-(2-                                                       hydroxy-3-nitrophenyl)propyl!benzoate (5.4 g) and methyl                      4- 3-(2-hydroxy-5-nitro-                                                      phenyl)propyl!benzoate (7.5 g).                                             d:                                                                              Methyl 4- 3-(2-benzyloxy-5-aminophenyl)propyl!benzoate was prepared           from methyl                                                                   4- 3-(2-benzyloxy-5-nitrophenyl)propyl!benzoate using the process             described in Example 2,                                                       note a.                                                                     e:                                                                              Methyl 4- 3-(2-benzyloxy-5-methylcarbonylaminophenyl)propyl!benzoate          was prepared                                                                  from methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate by the           method described                                                              in Example 2, note b.                                                       f:                                                                              Methyl 4- 3-(2-benzyloxy-5-ethoxycarbonylaminophenyl)propyl!benzoate          was prepared                                                                  from methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate by the           method described                                                              in Example 2, note b using ethyl chloroformate in the place of acetic         anhydride as the                                                              acylating agent.                                                            g:                                                                              Methyl 4- 3-(2-benzyloxy-5-phenylsulphonamidophenyl)propyl!benzoate was       prepared                                                                      from methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate as               follows:                                                                      To a mixture of methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate       (0.3 g)                                                                       and potassium carbonate (170 mg) was added benzenesulphonyl chloride          (0.15 ml) and the                                                             mixture stirred for 18 hours, poured into ethyl acetate (50 ml) and           washed with 1M HCl                                                            (50 ml), sodium bicarbonate (50 ml) and brine (50 ml). The organic            solution was dried                                                            (magnesium sulphate), filtered and evaporated. The residue was purified       by subjecting to                                                              chromatography on silica gel using ethyl acetate:hexane (3:7) as              eluant. There was thus                                                        obtained methyl 4- 3-(2-benzyloxy-5-phenylsulphonamidophenyl)propyl!benz      oate                                                                          (150 mg).                                                                   h:                                                                              Methyl 4- 3-(2-benzyloxy-5-(trifluoromethylcarbonylamino)-phenyl)propyl!      benzoate was                                                                  synthesised from methyl 4- 3-(2-benzyloxy-5-aminophenyl)propyl!benzoate       using the method                                                              described in Example 2, note b using trifluoromethylacetic anhydride in       the place of acetic                                                           anhydride as the acylating agent.                                             To a mixture of NaH (50% by weight in oil) (20 mg) in DMF (5 ml) was          added methyl 4- 3-                                                            (2-benzyloxy-5-(trifluoromethylcarbonylamino)phenyl)propyl!benzoate           (200 mg).                                                                     After 1 hour, MeI (0.2 ml) was added and the mixture stirred for 18           hours. The mixture                                                            was poured into 1M HCl (50 ml), and extracted with ethyl acetate (2           × 25 ml). The organics                                                  were washed with brine (50 ml), dried (magnesium sulphate), filtered          and evaporated. There was                                                     thus obtained methyl 4-(3-(2-benzyloxy-5-(N-methyl-trifluoromethylcarbon      ylamino)phenyl)-                                                              propyl!benzoate (200 mg). 4- 3-(2-Benzyloxy-5-methylaminophenyl)propyl!b      enzoic acid                                                                   was obtained from methyl 4- 3-(2-benzyloxy-5-(N-methyltrifluoromethylcar      bonyl-                                                                        amino)phenyl)propyl!benzoate by the standard hydrolysis method.             i:                                                                              Methyl 4- 3-(2-benzyloxy-5-(N,N-diethylamino)phenyl)propyl!-benzoate          was obtained from                                                             methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate as follows:           To a mixture of methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate       (250 mg)                                                                      in DMF (10 ml) was added potassium carbonate (200 mg) and ethyl iodide        (0.16 ml).                                                                    The mixture was stirred for 18 hours, poured into ethyl acetate (50 ml)       and washed with                                                               brine (50 ml), dried (magnesium sulphate), filtered and evaporated. The       residue was                                                                   purified by chromatography on silica gel using ethyl acetate:hexane           (3;7) as eluant. There was                                                    thus obtained methyl 4- 3-(2-benzyloxy-5-(N,N-diethylamino)phenyl)propyl      !benzoate                                                                     (150 mg).                                                                   j:                                                                              Methyl 4- 3-(2-hydroxy-5-acetylphenyl)propyl!benzoate was obtained from       methyl                                                                        4- 3-(2-hydroxyphenyl)propyl!benzoate as follows:                             To a cooled (0° C.) solution of aluminium chloride (311 mg) in         nitrobenzene (5 ml) was                                                       added methyl 4- 3-(2-hydroxyphenyl)propyl!-benzoate (0.6 g) then acetyl       chloride                                                                      (0.16 ml). The mixture was heated at 50° C. for 3 hours,               aluminium chloride (622 mg)                                                   added and the mixture was heated at 50° C. for a further 3             hours. The mixture was                                                        poured into 1M HCl (100 ml) and ethyl acetate (100 ml), the organic           layer washed with                                                             sodium bicarbonate (100 ml) and brine (100 ml), dried (magnesium              sulphate), filtered and                                                       evaporated. The residue was purified by subjecting to chromatography on       silica gel                                                                    using ethyl acetate:dichloromethane (0:100, 5:95 gradient) as eluant.         There was thus obtained                                                       methyl 4- 3-(2-hydroxy-5-acetylphenyl)propyl!benzoate (360 mg).             k:                                                                              Methyl 4- 3-(2-hydroxy-5-hexanoylphenyl)propyl!benzoate was obtained          from methyl                                                                   4- 3-(2-hydroxyphenyl)propyl!benzoate by the method described in note j       using hexanol                                                                 chloride in place of acetyl chloride.                                       l:                                                                              Methyl 4- 3-(2-benzyloxy-5-hexylphenyl)propyl!benzoate was obtained           from methyl                                                                   4- 3-(2-benzyloxy-5-hexanoylphenyl)propyl!-benzoate (synthesised from         methyl                                                                        4- 3-(2-hydroxy-5-hexanoylphenyl)-propyl!benzoate using the benzylation       method                                                                        described in Example 1B) as follows:                                          To a solution of methyl 4- 3-(2-benzyloxy-5-hexanoylphenyl)-propyl!benzo      ate                                                                           (280 mg) in trifluoroacetic acid (0.47 ml) was added triethylsilane           (0.49 ml)                                                                     and the mixture stirred for 18 hours.                                         Trifluoroacetic acid (0.47 ml) and triethylsilane (0.49 ml) were added        and the mixture                                                               stirred for a further 4 hours. The reaction mixture was purified by           subjecting to                                                                 chromatography on silica gel using dichloromethane as eluant. There was       thus obtained                                                                 methyl 4- 3-(2-benzyloxy-5-hexylphenyl)propyl!benzoate (210 mg).            m:                                                                              Methyl 4- 3-(2-hydroxy-5-bromophenyl)propyl!benzoate was obtained from        methyl                                                                        4- 3-(2-hydroxyphenyl)propyl!benzoate as follows:                             To a mixture of methyl 4-(3-(2-hydroxyphenyl)propyl!benzoate (1.5 g) in       chloroform (25 ml)                                                            was added tetrabutylammonium tribromide (3.12 g). The mixture was             stirred for                                                                   2 hours, washed with sodium thiosulphate (100 ml), and water (3 ×       100 ml),                                                                      dried (magnesium sulphate), filtered and evaporated. The residue was          purified by                                                                   chromatography on silica gel using ethyl acetate:hexane (3:7) as              eluant. There was thus                                                        obtained methy 4- 3-(2-hydroxy-5-bromophenyl)-propyl!-benzoate (1.9           g).                                                                         n:                                                                              Methyl 4- 3-(2-benzyloxy-5-cyanophenyl)propyl!benzoate was obtained           from methyl                                                                   4- 3-(2-benzyloxy-5-bromophenyl)propyl!benzoate as follows:                   A mixture of methyl 4- 3-(2-benzyloxy-5-bromophenyl)propyl!benzoate           (0.5 g) and CuCN                                                              (250 mg) in DMF (20 ml) was heated at reflux for 18 hours, poured into        ethylene                                                                      diamine (20 ml) and water (60 ml) and extracted with ethyl acetate (3         × 100 ml).                                                              The combined extracts were washed with brine (100 ml), dried (magnesium       sulphate), filtered                                                           and evaporated to give methyl 4- 3-(2-benzyloxy-5-cyanophenyl)propyl!ben      zoate (290 mg).                                                             o:                                                                              Methyl 4- 3-(2-hydroxy-5-formylphenyl)propyl!benzoate was obtained from       methyl                                                                        4- 3-(2-hydroxyphenyl)propyl!-benzoate as follows:                            To a mixture of methyl 4- 3-(2-hydroxyphenyl)propyl!-benzoate in              dichloromethane                                                               (12 g) at -5° C. was added titanium tetrachloride (1M solution         in                                                                            dichloromethane, 97.8 ml) then 1,1-dichloromethyl methylether (4.83 ml)       in                                                                            dichloromethane (50 ml). The mixture was stirred for 2 hours at               -5° C. then 3 hours                                                    at ambient temperature, poured into ice and concentrated HCl (2 ml) was       added.                                                                        The mixture was stirred with diethyl ether (200 ml) for 30 minutes, the       layers separated                                                              and the aqueous layer extracted with ethyl acetate (3 × 200 ml).        The combined                                                                  organic solutions were dried (magnesium sulphate), filtered and               evaporated.                                                                   The residue was purified by chromatography on silica gel using ethyl          acetate:                                                                      dichloromethane (0:100 to 10:90 gradient) as eluant. Two products were        isolated,                                                                     methyl 4- 3-(2-hydroxy-3-formylphenyl)propyl!-benzoate (2.40 g) eluted        first,                                                                        and methyl 4- 3-(2-hydroxy-5-formyl-phenyl)propyl!benzoate (6.39 g)           eluted second.                                                              p:                                                                              Methyl 4- 3-(2-benzyloxy-5-hydroxymethylphenyl)propyl!-benzoate was           obtained from                                                                 methyl 4- 3-(2-benzyloxy-5-formylphenyl)-propyl!benzoate as follows:          A mixture of methyl 4- 3-(2-benzyloxy-5-formylphenyl)-propyl!benzoate         (0.97 g)                                                                      and sodium borohydride (142 mg) in ethanol (10 ml) was stirred at             0° C. for 30 minutes                                                   at ambient temperature for 1 hour, the solvent was evaporated, the            residue mixed with ethyl                                                      acetate (100 ml) and washed with 1M HCl (100 ml), sodium bicarbonate          (100 ml) and brine                                                            (100 ml), dried (magnesium sulphate), filtered and evaporated. The            residue was purified                                                          by subjecting to chromatography on silica gel using ethyl                     acetate:dichloromethane                                                       (0:100 to 5:95 gradient) as eluant. There was thus obtained methyl            4- 3-(2-                                                                      benzyloxy-5-hydroxymethylphenyl)propyl!benzoate (0.94 g).                   q:                                                                              Methyl 4- 3-(2-benzyloxy-5-(acetyloxime)phenyl)propyl!-benzoate was           obtained                                                                      from methyl 4- 3-(2-benzyloxy-5-acetylphenyl)-propyl!benzoate as              follows:                                                                      A mixture of methyl 4- 3-(2-benzyloxy-5-acetylphenyl)-propyl!benzoate         (402 mg) and hydroxylamine hydrochloride (139 mg) in pyridine (5 ml)          was heated                                                                    at 60° C. for 2 hours, evaporated and the residue was purified         by subjecting to                                                              chromatography on silica gel using ethyl acetate:dichloromethane (5:95)       as eluant. There                                                              was thus obtained methyl 4- 3-(2-benzyloxy-5-(acetyloxime)phenyl)propyl!      -benzoate (0.38 g).                                                         r:                                                                              Methyl 4- 3-(2-benzyloxy-5-(formyloxime)phenyl)propyl!-benzoate was           obtained                                                                      from methyl 4- 3-(2-benzyloxy-5-formylphenyl)-propyl!benzoate by a            similar method                                                                to that described in note q.                                                s:                                                                              Methyl 4- 3-(2-benzyloxy-5-(O-methylacetyloxime)phenyl)-propyl!benzoate       was obtained                                                                  from methyl 4- 3-(2-benzyloxy-5-(acetyloxime)-phenyl)propyl!benzoate as       follows:                                                                      A mixture of methyl 4- 3-(2-benzyloxy-5-(acetyloxime)-phenyl)propyl!benz      oate                                                                          (390 mg) and NaH (50% by weight in oil) (60 mg) was stirred for 30            minutes. MeI (0.23 ml)                                                        was added and the mixture stirred for 2 hours. A further 100 mg of NaH        (50% by weight in                                                             oil) and 1 ml of MeI was added and the mixture stirred for 18 hours,          poured into 1M HCl                                                            (100 ml) and extracted with ethyl acetate (100 ml) and the solvent            evaporated. The residue                                                       was purified by chromatography on silica gel using dichloromethane:hexan      e (0:100                                                                      to 80:20 gradient) as eluant. There was thus obtained methyl                  4- 3-(2-benzyloxy-5-                                                          (acetyloxime)phenyl)propyl!benzoate (150 mg).                               t:                                                                              Methyl 4- 2-(2-hydroxy-5-nitrophenyl)ethyl!benzoate was prepared from         methyl 4- 3-(2-                                                               hydroxyphenyl)ethyl!benzoate by a similar method to that described in         note c.                                                                     u:                                                                              Methyl 4- 3-(2-benzyloxy-5-methanesulphinyl)phenyl)propyl!benzoate was        obtained from                                                                 the corresponding methylthio compound (see example 7) by a modification       of the method                                                                 in example 49 in which mCPBA was added at 0° C. and the reaction       terminated                                                                    when all the methylthio compound was consumed.                              v:                                                                              Methyl 4- 3-(2-benzyloxy-5-methanesulphonylphenyl)propyl!benzoate             ester                                                                         was obtained from the corresponding methylthio compound (see example 7)       by a similar                                                                  method to that of Example 49.                                               w:                                                                              The ethyl ester was obtained using a similar method to that described         in Example 45                                                                 (compound 51).                                                              x:                                                                              The ethyl ester was obtained using a similar method to that described         in Example 45                                                                 (compound 52).                                                              y:                                                                              Methyl 4- 3-(2-hydroxy-5,6,7,8-tetrahydro-1-naphthyl)propyl!benzoate          was obtained as                                                               a by-product from the reduction of methyl 4- 3-(2-benzyloxy-1-naphthyl)-      2-propenyl!benzoate                                                           and methyl 4- 3-(2-benzyloxy-1-naphthyl)-1-propenyl!benzoate (mixture         of double bond isomers) obtained as an intermediate to compound 34            (Example 3).                                                                z:                                                                              Methyl 4- 3-(2-hydroxy-5-(2-methylpropionyl)phenyl)propyl!benzoate was        obtained                                                                      from methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate using and                   2-methylpropionyl chloride                                                    using the method described in Example 3 Footnote j.                         aa:                                                                             The methyl 4- 3-(2-benzyloxy-5-hydroxyiminoalkylphenyl)propyl!-benzoates       were                                                                         obtained from the corresponding methyl 4- 3-(2-benzyloxy-5-alkanoylpheny      l)propyl!benzoate                                                             compounds by a similar method to that of Example 3, Footnote q as a           mixture of the Z and                                                          E isomers.                                                                  ab:                                                                             Methyl 4- 3-(2-hydroxy-5-propionylphenyl)propyl!benzoate was obtained         from methyl                                                                   4- 3-(2-hydroxyphenyl)propyl!benzoate and EtCOCl using a similar method       to that                                                                       of Example 3, Footnote j.                                                   ac:                                                                             Methyl 4- 3-(2-hydroxy-5-benzoylphenyl)propyl!benzoate was obtained           from methyl                                                                   4- 3-(2-hydroxyphenyl)propyl!benzoate and PhCOCl using a similar method       to that                                                                       of Example 3, Footnote j.                                                   ad:                                                                             Methyl 4- 3-(2-benzyloxy-5-(1-semicarbazonoethyl)phenyl)propyl!benzoate       (mpt.                                                                         158-160° C.) was obtained as follows:-                                 A mixture of methyl 4- 3-(2-benzyloxy-5-acetylphenyl)propyl!benzoate          (0.5 g),                                                                      NH.sub.2 CONHNH.sub.2. HCl (0.14 g) and pyridine (5 drops) in methanol        (20 ml) was heated                                                            under reflux for 90 minutes, cooled and the resulting white solid             isolated by filtration                                                        and washed with ethanol and ether.                                          ae:                                                                             Methyl 4- 3-(2-benzyloxy-5-(1-hydrazonoethyl)phenyl)propyl!benzoate           was obtained as follows:-                                                     A mixture of methyl 4- 3-(2-benzyloxy-5-acetylphenyl)propyl!benzoate          (0.5 g) and                                                                   hydrazine hydrate (1.2 ml) in ethanol (20 ml) was heated at reflux in a       soxhlet                                                                       apparatus using Na.sub.2 SO.sub.4 as the drying agent, for 3 hours. The       solvent was                                                                   evaporated and the residue extracted with EtOAc and washed with               saturated aqueous                                                             NaHCO.sub.3 solution.                                                       af:                                                                             Methyl 4- 3-(2-benzyloxy-5-(1-phenylhydrazonoethyl)phenyl)propyl!benzoat      e was                                                                         obtained using a similar method to that of Example 3 Footnote ae, with        the modification                                                              that 3 drops of glacial acetic acid were added to the reaction                mixture.                                                                    ag:                                                                             Methyl 4- 3-(2-benzyloxy-5-methoxymethylphenyl)propyl!benzoate was            obtained                                                                      as follows:-                                                                  To a solution of methyl 4- 3-(2-benzyloxy-5-hydroxymethylphenyl)propyl!b      enzoate                                                                       (5.31 g) in methanol (100 ml) was added 4-methylbenzenesulphonic acid         (3.11 g).                                                                     The reaction was heated at reflux for 18 hours, the solvent evaporated,       the residue                                                                   dissolved in EtOAc, washed with brine and the solvent evaporated to           give methyl                                                                   4- 3-(2-benzyloxy-5-methoxymethylphenyl)propyl!benzoate (3.64 g).           ah:                                                                             To a stirred solution of methyl 4- 3-(2-benzyloxy-5-hydroxymethyl-            phenyl)propyl!benzoate (1.57 g) in CH.sub.2 Cl (15 ml), at -20°        C., was                                                                       added methanesulphonyl chloride (0.37 ml), triethylamine (0.84 ml) and        DMAP (0.29 g).                                                                The reaction was stirred at -20° C. for 5 hours, diluted with          CH.sub.2 Cl.sub.2                                                             (50 ml) and washed with water, saturated aqueous NaHCO.sub.3 and brine.       The organic                                                                   layer was dried (MgSO.sub.4), filtered and evaporated to give a white         solid (1.37 g).                                                               To the white solid (1.37 g) in DMF (10 ml) was added sodium                   thiomethoxide (0.24 g)                                                        in DMF (10 ml). The reaction mixture was stirred for 8 hours, the             solvent evaporated                                                            and the residue washed with water and extracted with ethyl acetate. The       organic solution                                                              was washed with brine, dried (MgSO.sub.4), filtered and evaporated, to        give methyl                                                                   4- 3-(2-benzyloxy-5-methanethiomethylphenyl)propyl!benzoate (0.68 g)          which crystallised                                                            on standing.                                                                ai:                                                                             Methyl 4- 3-(2-benzyloxy-5-methanesulphinylmethylphenyl)propyl!benzoate       and                                                                           methyl 4- 3-(2-benzyloxy-5-methanesulphonylmethylphenyl)propyl!benzoate       were                                                                          prepared as a mixture from the methyl 4- 3-(2-benzyloxy-5-methanethiomet      hylphenyl)                                                                    propyl!benzoate using a similar method to that of Example 49 and              separated by MPLC,                                                            eluting with ethyl acetate.                                                 aj:                                                                             Methyl 4- 3-(2-benzyloxy-5-(oxazol-5-yl)phenyl!benzoate was prepared as       follows:-                                                                     To a mixture of methyl 4- 3-(2-benzyloxy-5-formylphenyl)propyl!benzoate       (0.75 g)                                                                      and potassium carbonate (0.696 g) in methanol (60 ml) was added               tosylmethyl isocyanide                                                        (0.54 g). The reaction was heated at reflux for 30 minutes, the solvent       evaporated                                                                    and the residue partitioned between water and CH.sub.2 Cl.sub.2. The          CH.sub.2 Cl.sub.2 was washed                                                  with H.sub.2 O, dried (MgSO.sub.4), filtered and evaporated. The              residue was purified by MPLC,                                                 eluting with 3% EtOAC/CH.sub.2 Cl.sub.2 to give methyl                        4- 3-(2-benzyloxy-5-(oxaxol-5-                                                yl)phenyl!benzoate (290 mg).                                                ak:                                                                             Methyl 4- 3-(2-benzyloxy-5-(diethylamino)phenyl)propyl!benzoate was           prepared as follows:-                                                         To a mixture of methyl 4- 3-(2-benzyloxy-5-aminophenyl)propyl!benzoate        (250 mg)                                                                      in DMF (5 ml) was added potassium carbonate (0.2 g) and iodoethane            (0.16 ml). The                                                                reaction was stirred for 18 hours, diluted with EtOAc, washed with            water and brine, dried                                                        (MgSO.sub.4), filtered and evaporated. The residue was purified by            flash chromatography                                                          to give the methyl 4- 3-(2-benzyloxy-5-(diethylamino)phenyl)propyl!benzo      ate                                                                           as an oil (150 mg).                                                         al:                                                                             Methyl 4- 2-(2-benzyloxy-5-bromophenyl)ethyl!benzoate was prepared from       methyl                                                                        4- 2-(2-hydroxyphenyl)ethyl!benzoate using a similar method to that of        Example 3                                                                     Footnote m.                                                             

a:- (4-Carboxyphenylmethyl)triphenylphosphonium bromide was prepared inthe standard way from 4-(bromomethyl)benzoic acid andtriphenylphosphine.

b:- (4-Carboxymethylphenylmethyl)triphenylphosphonium bromide preparedin the standard way from 4-(bromomethyl)phenylacetic acid andtriphenylphosphine.

c:- Methyl 4- 3-(2-hydroxy-5-nitrophenyl)propyl!benzoate was preparedfrom methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate (see Example 1) asfollows:

Nitric acid (15M, 3.13 ml) was added to acetic anhydride 12.52 ml) at 0°C. and the mixture stirred for 15 minutes, then added to a stirredsolution of methyl 4- 3-(2-hydroxyphenyl)-propyl!benzoate (12.89 g) inacetic anhydride (300 ml) at 0° C. and stirred for 18 hours. The solventwas evaporated and the resulting yellow oil purified by chromatographyon silica gel using ethyl acetate: hexane (1:9 to 1:1 gradient) aseluant to give methyl 4- 3-(2-hydroxy-3-nitrophenyl)propyl!benzoate (5.4g) and methyl 4- 3-(2-hydroxy-5-nitrophenyl)propyl!benzoate (7.5 g).

d:- Methyl 4- 3-(2-benzyloxy-5-aminophenyl)propyl!benzoate was preparedfrom methyl 4- 3-(2-benzyloxy-5-nitrophenyl)propyl!benzoate using theprocess described in Example 2, note a.

e:- Methyl 4- 3-(2-benzyloxy-5-methylcarbonylaminophenyl)propyl!benzoate was prepared from methyl 4-3-(2-benzyloxy-5-aminophenyl)-propyl! benzoate by the method describedin Example 2, note b.

f:- Methyl 4- 3-(2-benzyloxy-5-ethoxycarbonylaminophenyl)propyl!benzoate was prepared from methyl 4-3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate by the method described inExample 2, note b using ethyl chloroformate in the place of aceticanhydride as the acylating agent.

g:- Methyl 4- 3-(2-benzyloxy-5-phenylsulphonamidophenyl)propyl!benzoatewas prepared from methyl 4-3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate as follows:

To a mixture of methyl 4- 3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate(0.3 g) and potassium carbonate (170 mg) was added benzenesulphonylchloride (0.15 ml) and the mixture stirred for 18 hours, poured intoethyl acetate (50 ml) and washed with 1M HCl (50 ml), sodium bicarbonate(50 ml) and brine (50 ml). The organic solution was dried (magnesiumsulphate), filtered and evaporated. The residue was purified bysubjecting to chromatography on silica gel using ethyl acetate: hexane(3:7) as eluant. There was thus obtained methyl4-(3-(2-benzyloxy-5-phenylsulphonamidophenyl)propyl)benzoate (150 mg).

h:- Methyl 4-3-(2-benzyloxy-5-(trifluoromethylcarbonylamino)-phenyl)propyl!benzoatewas synthesised from methyl 4-3-(2-benzyloxy-5-aminophenyl)propyl!benzoate using the method describedin Example 2, note b using trifluoromethylacetic anhydride in the placeof acetic anhydride as the acylating agent.

To a mixture of NaH (50% by weight in oil) (20 mg) in DMF (5 ml) wasadded methyl 4-3-(2-benzyloxy-5-(trifluoromethylcarbonylamino)phenyl)propyl!benzoate(200 mg). After 1 hour, MeI (0.2 ml) was added and the mixture stirredfor 18 hours. The mixture was poured into 1M HCl (50 ml), and extractedwith ethyl acetate (2×25 ml). The organics were washed with brine (50ml), dried (magnesium sulphate), filtered and evaporated. There was thusobtained methyl 4-3-(2-benzyloxy-5-(N-methyl-trifluoromethylcarbonylamino)phenyl)-propyl!benzoate(200 mg).

4- 3-(2-Benzyloxy-5-methylaminophenyl)propyl!benzoic acid was obtainedfrom methyl 4-3-(2-benzyloxy-5-(N-methyltrifluoromethylcarbonylamino)phenyl)propyl)benzoateby the standard hydrolysis method.

i:- Methyl 4- 3-(2-benzyloxy-5-(N,N-diethylamino)phenyl)propyl!-benzoatewas obtained from methyl 4-3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate as follows:

To a mixture of methyl 4-(3-(2-benzyloxy-5-aminophenyl)-propyl!benzoate(250 mg) in DMF (10 ml) was added potassium carbonate (200 mg) and ethyliodide (0.16 ml). The mixture was stirred for 18 hours, poured intoethyl acetate (50 ml) and washed with brine (50 ml), dried (magnesiumsulphate), filtered and evaporated. The residue was purified bychromatography on silica gel using ethyl acetate: hexane (3;7) aseluant. There was thus obtained methyl 4-3-(2-benzyloxy-5-(N,N-diethylamino)phenyl)propyl)benzoate (150 mg).

j:- Methyl 4- 3-(2-hydroxy-5-acetylphenyl)propyl!benzoate was obtainedfrom methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate as follows:

To a cooled (0° C.) solution of aluminium chloride (311 mg) innitrobenzene (5 ml) was added methyl 4-3-(2-hydroxyphenyl)propyl!-benzoate (0.6 g) then acetyl chloride (0.16ml). The mixture was heated at 50° C. for 3 hours, aluminium chloride(622 mg) added and the mixture was heated at 50° C. for a further 3hours. The mixture was poured into 1M HCl (100 ml) and ethyl acetate(100 ml), the organic layer washed with sodium bicarbonate (100 ml) andbrine (100 ml), dried (magnesium sulphate), filtered and evaporated. Theresidue was purified by subjecting to chromatography on silica gel usingethyl acetate: dichloromethane (0:100, 5:95 gradient) as eluant. Therewas thus obtained methyl 4- 3-2-hydroxy-5-acetylphenyl)propyl!benzoate(360 mg).

k:- Methyl 4- 3-(2-hydroxy-5-hexanoylphenyl)propyl!benzoate was obtainedfrom methyl 4-(3-(2-hydroxyphenyl)propyl!benzoate by the methoddescribed in note j using hexanoyl chloride in place of acetyl chloride.

l:- Methyl 4- 3-(2-benzyloxy-5-hexylphenyl)propyl!benzoate was obtainedfrom methyl 4- 3-2-benzyloxy-5-hexanoylphenyl)propyl!-benzoate(synthesised from methyl 4-3-(2-hydroxy-5-hexanoylphenyl)-propyl!benzoate using the benzylationmethod described in Example 1 B) as follows:

To a solution of methyl 4-3-(2-benzyloxy-5-hexanoylphenyl)-propyl!benzoate (280 mg) intrifluoroacetic acid (0.47 ml) was added triethylsilane (0.49 ml) andthe mixture stirred for 18 hours. Trifluoroacetic acid (0.47 ml) andtriethylsilane (0.49 ml) were added and the mixture stirred for afurther 4 hours. The reaction mixture was purified by subjecting tochromatography on silica gel using dichloromethane as eluant. There wasthus obtained methyl 4- 3-(2-benzyloxy-5-hexylphenyl)propyl!benzoate(210 mg).

m:- Methyl 4- 3-(2-hydroxy-5-bromophenyl)propyl!benzoate was obtainedfrom methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate as follows:

To a mixture of methyl 4- 3-(2-hydroxyphenyl)propyl! benzoate (1.5 g) inchloroform (25 ml) was added tetrabutylammonium tribromide (3.12 g). Themixture was stirred for 2 hours, washed with sodium thiosulphate (100ml), and water (3×100 ml), dried (magnesium sulphate), filtered andevaporated. The residue was purified by chromatography on silica gelusing ethyl acetate:hexane (3:7) as eluant. There was thus obtainedmethy 4- 3-(2-hydroxy-5-bromophenyl)-propyl!benzoate (1.9 g).

n:- Methyl 4- 3-(2-benzyloxy-5-cyanophenyl)propyl!benzoate was obtainedfrom methyl 4- 3-(2-benzyloxy-5-bromophenyl)propyl!-benzoate as follows:

A mixture of methyl 4- 3-(2-benzyloxy-5-bromophenyl)propyl!-benzoate(0.5 g) and CuCN (250 mg) in DMF (20 ml) was heated at reflux for 18hours, poured into ethylene diamine (20 ml) and water (60 ml) andextracted with ethyl acetate (3×100 ml). The combined extracts werewashed with brine (100 ml), dried (magnesium sulphate), filtered andevaporated to give methyl 4-3-(2-benzyloxy-5-cyanophenyl)propyl!-benzoate (290 mg).

o:- Methyl 4-(3-(2-hydroxy-5-formylphenyl)propyl!benzoate was obtainedfrom methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate as follows:

To a mixture of methyl 4- 3-(2-hydroxyphenyl)propyl!-benzoate indichloromethane (12 g) at -5° C. was added titanium tetrachloride (1 Msolution in dichloromethane, 97.8 ml) then 1,1-dichloromethylmethylether (4.83 ml) in dichloromethane (50 ml). The mixture wasstirred for 2 hours at -5° C. then 3 hours at ambient temperature,poured into ice and concentrated HCl (2 ml) was added. The mixture wasstirred with diethyl ether (200 ml) for 30 minutes, the layers separatedand the aqueous layer extracted with ethyl acetate (3×200 ml). Thecombined organic solutions were dried (magnesium sulphate), filtered andevaporated. The residue was purified by chromatography on silica gelusing ethyl acetate: dichloromethane (0:100 to 10:90 gradient) aseluant. Two products were isolated, methyl 4-3-(2-hydroxy-3-formylphenyl)propyl!- benzoate (2.40 g) eluted first, andmethyl 4- 3-(2-hydroxy-5-formyl-phenyl) propyl!benzoate (6.39 g) elutedsecond.

p:- Methyl 4- 3-(2-benzyloxy-5-hydroxymethylphenyl)propyl!-benzoate wasobtained from methyl 4- 3-(2-benzyloxy-5-formylphenyl)-propyl!benzoateas follows:

A mixture of methyl 4- 3-(2-benzyloxy-5-formylphenyl)-propyl!benzoate(0.97 g) and sodium borohydride (142 mg) in ethanol (10 ml) was stirredat 0° C. for 30 minutes at ambient temperature for 1 hour, the solventwas evaporated, the residue mixed with ethyl acetate (100 ml) and washedwith 1M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml),dried (magnesium sulphate), filtered and evaporated. The residue waspurified by subjecting to chromatography on silica gel using ethylacetate: dichloromethane (0:100 to 5:95 gradient) as eluant. There wasthus obtained methyl 4-3-(2-benzyloxy-5-hydroxymethylphenyl)propyl!benzoate (0.94 g)

q:- Methyl 4- 3-(2-benzyloxy-5-(acetyloxime phenyl)propyl!-benzoate wasobtained from methyl 4- 3-(2-benzyloxy-5-acetylphenyl)-propyl!benzoatepropyl!benzoate as follows:

A mixture of methyl 4- 3-(2-benzyloxy-5-acetylphenyl)-propyl!benzoate(402 mg) and hydroxylamine hydrochloride (139 mg) in pyridine (5 ml) washeated at 60° C. for 2 hours, evaporated and the residue was purified bysubjecting to chromatography on silica gel using ethyl acetate:dichloromethane (5:95) as eluant. There was thus obtained methyl 4-3-(2-benzyloxy-5-(acetyloxime)phenyl)-propyl!benzoate (0.38 g).

r:- Methyl 4- 3-(2-benzyloxy-5-(formyloxime)phenyl)propyl!-benzoate wasobtained from methyl 4- 3-(2-benzyloxy-5-formylphenyl)-propyl!benzoateby a similar method to that described in note q.

s:- Methyl 4-3-(2-benzyloxy-5-(O-methylacetyloxime)phenyl)-propyl!benzoate wasobtained from methyl 4--(2-benzyloxy-5-(acetyloxime)-phenyl)propyl!benzoate as follows:

A mixture of methyl 4-3-(2-benzyloxy-5-5acetyloxime)-phenyl)propyl!benzoate (390 mg) and NaH(50% by weight in oil) (60 mg) was stirred for 30 minutes. MeI (0.23 ml)was added and the mixture stirred for 2 hours. A further 100 mg of NaH(50% by weight in oil) and 1 ml of MeI was added and the mixture stirredfor 18 hours, poured into 1M HCl (100 ml) and extracted with ethylacetate (100 ml) and the solvent evaporated. The residue was purified bychromatography on silica gel using dichloromethane: hexane (0:100 to80:20 gradient) as eluant. There was thus obtained

methyl4- 3-(2-benzyloxy-5-(acetyloxime)pheny)propyl!benzoate (150 mg).

t:- Methyl 4- 2-(2-hydroxy-5-nitrophenyl)ethyl!benzoate was preparedfrom methyl 4- 3-(2-hydroxyphenyl)ethyl!benzoate by a similar method tothat described in note c.

u:- Methyl 4- 3-(2-benzyloxy-5-methanesulphinyl)phenyl) propyl!benzoatewas obtained from the corresponding methylthio compound (see example 7)by a modification of the method in example 49 in which mCPBA was addedat 0° C. and the reaction terminated when all the methylthio compoundwas consumed.

v:- Methyl 4- 3-(2-benzyloxy-5-methanesulphonylphenyl) propyl!benzoateester was obtained from the corresponding methylthio compound (seeexample 7) by a similar method to that of Example 49.

w:- The ethyl ester was obtained using a similar method to thatdescribed in Example 45 (compound 51).

x:- The ethyl ester was obtained using a similar method to thatdescribed in Example 45 (compound 52).

y:- Methyl 4- 3-(2-hydroxy-5,6,7,8-tetrahydro-1-naphthyl)propyl!benzoate was obtained as a by-product from the reduction ofmethyl 4- 3-(2-benzyloxy- -naphthyl)-2-propenyl!benzoate and methyl 4-3-(2-benzyloxy-1-naphthyl)-1-propenyl!benzoate (mixture of double bondisomers) obtained as an intermediate to compound 34 (Example 3).

z:- Methyl 4- 3-(2-hydroxy-5-(2-methylpropionyl)phenyl) propyl!benzoatewas obtained from methyl 4- 3-(2-hydroxyphenyl) propyl!benzoate usingand 2-methylpropionyl chloride using the method described in Example 3Footnote j.

aa:- The methyl 4- 3-(2-benzyloxy-5-hydroxyiminoalkylphenyl)propyl!-benzoates were obtained from the corresponding methyl 4-3-(2-benzyloxy-5-alkanoylphenyl)propyl!benzoate compounds by a similarmethod to that of Example 3, Footnote q, as a mixture of the Z and Eisomers.

ab:- Methyl 4- 3-(2-hydroxy-5-propionylphenyl)propyl!benzoate wasobtained from methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate and EtCOClusing a similar method to that of Example 3, Footnote j.

ac:- Methyl 4- 3-(2-hydroxy-5-benzoylphenyl)propyl!benzoate was obtainedfrom methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate and PhCOCl using asimilar method to that of Example 3, Footnote j.

ad:- Methyl 4- 3-(2-benzyloxy-5-(1-semicarbazonoethyl)phenyl)propyl!benzoate (mpt. 158°-160° C.) was obtained as follows:--

A mixture of methyl 4- 3-(2-benzyloxy-5-acetylphenyl)propyl!benzoate(0.5 g), NH₂ CONHNH₂. HCl 0.14 g) and pyridine (5 drops) in methanol (20ml) was heated under reflux for 90 minutes, cooled and the resultingwhite solid isolated by filtration and washed with ethanol and ether.

ae:- Methyl 4- 3-(2-benzyloxy-5-(1-hydrazonoethyl)phenyl)propyl!benzoate was obtained as follows:--

A mixture of methyl 4- 3-(2-benzyloxy-5-acetylphenyl)propyl!benzoate(0.5 g) and hydrazine hydrate (1.2 ml) in ethanol (20 ml) was heated atreflux in a soxhlet apparatus using Na₂ SO₄ as the drying agent, for 3hours. The solvent was evaporated and the residue extracted with EtOAcand washed with saturated aqueous NaHCO₃ solution.

af:- Methyl 4- 3-(2-benzyloxy-5-(1-phenylhydrazonoethyl)phenyl)propyl!benzoate was obtained using a similar method to that ofExample 3 Footnote ae, with the modification that 3 drops of glacialacetic acid were added to the reaction mixture.

ag:- Methyl 4- 3-(2-benzyloxy-5-methoxymethylphenyl) propyl!benzoate wasobtained as follows:--

To a solution of methyl 4- 3-(2-benzyloxy-5-hydroxymethylphenyl)propyl!benzoate (5.31 g) in methanol (100 ml) was added4-methylbenzenesulphonic acid (3.11 g). The reaction was heated atreflux for 18 hours, the solvent evaporated, the residue dissolved inEtOAc, washed with brine and the solvent evaporated to give methyl 4-3-(2-benzyloxy-5-methoxymethylphenyl)propyl!benzoate (3.64 g).

ah:- To a stirred solution of methyl 4-3-(2-benzyloxy-5-hydroxymethylphenyl)propyl!benzoate (1.57 g) in CH₂ Cl₂(15 ml), at -20° C., was added methanesulphonyl chloride (0.37 ml),triethylamine (0.84 ml) and DMAP (0.29 g) . The reaction was stirred at-20° C. for 5 hours, diluted with CH₂ Cl₂ (50 ml) and washed with water,saturated aqueous NaHCO₃ and brine. The organic layer was dried (MgSO₄),filtered and evaporated to give a white solid (1.37 g). To the whitesolid (1.37 g) in DMF (10 ml) was added sodium thiomethoxide (0.24 g) inDMF (10 ml). The reaction mixture was stirred for 8 hours, the solventevaporated and the residue washed with water and extracted with ethylacetate. The organic solution was washed with brine, dried (MgSO₄),filtered and evaporated, to give methyl 4-3-(2-benzyloxy-5-methanethiomethylphenyl)propyl!benzoate (0.68 g) whichcrystallised on standing.

ai:- 4ethyl 4- 3-(2-benzyloxy-5-methanesulphinylmethylphenyl)propyl!benzoate and methyl 4-3-(2-benzyloxy-5-methanesulphonylmethylphenyl)propyl!benzoate wereprepared as a mixture from the methyl 4-3-(2-benzyloxy-5-methanethiomethylphenyl) propyl!benzoate using asimilar method to that of Example 49 and separated by MPLC, eluting withethyl acetate.

aj:- Methyl 4- 3-(2-benzyloxy-5-(oxazol-5-yl)phenyl!benzoate wasprepared as follows:-

To a mixture of methyl 4- 3-(2-benzyloxy-5-formylphenyl) propyl!benzoate(0.75 g) and potassium carbonate (0.696 g) in methanol (60 ml) was addedtosylmethyl isocyanide (0.54 g). The reaction was heated at reflux for30 minutes, the solvent evaporated and the residue partitioned betweenwater and CH₂ Cl₂. The CH₂ Cl₂ was washed with H₂ O, dried (MgSO₄),filtered and evaporated. The residue was purified by MPLC, eluting with3% EtOAc/CH₂ Cl₂ to give methyl 4-3-(2-benzyloxy-5-(oxazol-5-yl)phenyl!benzoate (290 mg).

ak:- Methyl 4- 3-(2-benzyloxy-5-(diethylamino)phenyl) propyl!benzoatewas prepared as follows:-

To a mixture of methyl 4- 3-(2-benzyloxy-5-aminophenyl) propyl!benzoate(250 mg) in DMF (5 ml) was added potassium carbonate (0.2 g) andiodoethane (0.16 ml). The reaction was stirred for 18 hours, dilutedwith EtOAc, washed with water and brine, dried (MgSO₄), filtered andevaporated. The residue was purified by flash chromatography to give themethyl 4- 3-(2-benzyloxy-5-(diethylamino) phenyl)propyl!benzoate as anoil (150 mg).

al:- Methyl 4- 2-(2-benzyloxy-5-bromophenyl)ethyl)benzoate was preparedfrom methyl 4- 2-(2-hydroxyphenyl)ethyl!benzoate using a similar methodto that of Example 3 Footnote m.

EXAMPLE 4

4- 3-(2-Benzyloxy-5-hydroxyphenyl)propyl!benzoic acid

(A) A mixture of benzyl 4-3-(2-benzyloxy-5-(t-butylcarbonyloxyphenyl)propyl!benzoate and 2M NaOH(8 ml) in ethanol (20 ml) was stirred for 18 hours, a further 4 ml of 2M NaOH was added and the reaction stirred for 3 hours. The solvent wasevaporated, and the residue mixed with 1M HCl and extracted with ethylacetate (100 ml). The solvent was evaporated and the residue waspurified by chromatography on silica gel using ethyl acetate hexane (1;1) then methanol as eluant. There was thus obtained4-(3-(2-benzyloxy-5-hydroxyphenyl)propyl!benzoic acid (700 mg) mp.170°-171° C.

Benzyl 4- 3-(2-benzyloxy-5-(t-butylcarbonyloxy)phenyl)-propyl!benzoatewas prepared as follows:

(B) To a mixture of 2,5-dihydroxybenzaldehyde (10 g) in dichloromethane(50 ml) at 0° C. was added triethylamine (5 ml) and pivaloyl chloride(4.4 ml). The mixture was stirred at room temperature for 18 hours,filtered and the filtrates washed with 2M HCl (100 ml), brine (100 ml)and sodium bicarbonate (100 m), dried (magnesium sulphate) filtered andevaporated. The residue was purified by chromatography on silica gelusing dichloromethane:hexane (0:1 to 1:1 gradient) then ethylacetate:hexane (1:9 to 3:7 gradient) as eluants to give2-hydroxy-5-(t-butylcarbonyloxy)benzaldehyde (4 g) and some2,5-dihydroxy-benzaldehyde.

(C) To a mixture of (4-carboxyphenyl)ethyl triphenylphosphonium bromide(see Example 3, note a) (6.04 g) in THF was added lithiumhexamethyldisilazide (38 ml, 1.0M solution in THF). The mixture wasstirred for 1 hour, and 2-hydroxy-5-(t-butylcarbonyloxy)benzaldehyde(2.6 g) was added, the mixture stirred for 18 hours, poured into 1M HCl(200ml) and extracted with ethyl acetate (3×100 ml). The combinedorganics were washed with brine (100 ml), dried (magnesium sulphate)filtered and evaporated. The residue was purified by chromatography onsilica gel using ethyl acetate:hexane (1:9 to 8:2 gradient) as eluant.This material (3 g) was mixed with ethanol (300 ml) and 10% Pd-carbon(0.5 g) and stirred under 1 atm. of hydrogen for 18 hours. The mixturewas filtered and the filtrate evaporated. There was thus obtained 4-3-(2-hydroxy-5-(t-butyl-carbonyloxy)phenyl)propyl!benzoic acid (3 g).

(D) To a mixture of 4-3-(2-hydroxy-5-(t-butylcarbonyloxy)phenyl)propyl!benzoic acid (3 g) andpotassium carbonate (3.5 g) in DMF (10 ml) was added benzyl bromide(2.97 ml). The mixture was stirred for 18 hours, poured into ethylacetate (100 ml) and water (100 ml). The organic solution was washedwith brine (100 ml), dried (magnesium sulphate) filtered and evaporated.The residue was purified by subjecting to chromatography on silica gelusing ethyl acetate:hexane (1:9) as eluant. There was thus obtainedbenzyl 4- 3-(2-benzyloxy-5-(t-butylcarbonyloxy) phenyl)propyl!benzoate(2 g)

EXAMPLE 5

4- 3-(2-Benzyloxy-5-allyloxyphenyl)propyl!benzoic acid

(A) Allyl 4- 3-(2-benzyloxy-5-(allyloxy)phenyl)-propyl!benzoate wasconverted to 4- 3-(2-benzyloxy-5-(allyl-oxy)phenyl)propyl!benzoic acidmp. 96°-97° C., using the method described in Example 4 for theconversion of benzyl 4-3-(2-benzyloxy-5-(t-butylcarbonyloxy)phenyl)propyl!benzoate to 4-3-(2-benzyloxy-5-hydroxyphenyl)propyl!benzoic acid.

Allyl 4- 3-(2-benzyloxy-5-(allyloxy)phenyl)propyl! benzoate was preparedas follows:

(B) To a mixture of 4- 3-(2-benzyloxy-5-hydroxyphenyl)propyl!- benzoicacid (150 mg) (prepared as described in Example 4) and potassiumcarbonate (125 mg) in DMF (5 ml) was added allyl bromide (0.076 ml). Themixture was stirred for 18 hours, then potassium carbonate (125 mg) andallyl bromide (0.076 ml) were added and the mixture stirred for afurther 18 hours. The mixture was poured into water (50 ml) andextracted with ethyl acetate (2×20 ml). The combined organics solutionswere washed with brine (25 ml) and sodium bicarbonate (25 ml), dried(magnesium sulphate) filtered and evaporated. There was thus obtainedallyl 4- 3-(2-benzyloxy-5-(allyloxy)phenyl)propyl!benzoate (150 mg).

EXAMPLE 6

4- 3-(2-Benzyloxy-5-carbamoylmethoxyphenyl)propyl!benzoic acid

(A) Methyl 4- 3-(2-benzyloxy-5-(carbamoylmethoxy)phenyl)propyl! benzoatewas converted to 4-3-(2-benzyloxy-5-(carboxymethoxy)phenyl)propyl!benzoic acid mp.156°-157° C., using the method described in Example 4 for the conversionof benzyl 4- 3-(2-benzyloxy-5-(t-butylcarbonyloxy)phenyl)propyl!benzoateto 4- 3-(2-benzyloxy-5-hydroxyphenyl)propyl!benzoic acid.

Methyl 4- 3-(2-benzyloxy-5-(carbamoylmethoxy)phenyl)-propyl! benzoatewas prepared from 4- 3-(2-benzyloxy-5-hydroxy-phenyl)propyl!benzoic acid(Example 4) as follows:

(B) To a mixture of 4- 3-(2-benzyloxy-5-hydroxyphenyl)propyl!-benzoicacid (225 mg) in methanol (25 ml) at 0° C. was added dropwise thionylchloride (0.05 ml). The mixture was stirred for 18 hours, and a further0.05 ml of thionyl chloride was added. After 4 hours the solvent wasevaporated and the residue dissolved in ethyl acetate (100 ml) andwashed with sodium bicarbonate (25 ml) and brine (25 ml), dried(magnesium sulphate) filtered and evaporated. There was thus obtainedmethyl 4- 3-(2-benzyloxy-5-hydroxyphenyl)propyl!benzoate (250 mg).

(C) To a mixture of methyl 4-3-(2-benzyloxy-5-hydroxyphenyl)propyl!benzoate (510 mg) and potassiumcarbonate in DMF (10 ml) was added bromoacetamide (384 mg). The reactionwas stirred for 48 hours, poured into ethyl acetate (50 ml), washed with1M HCl (50 ml) and brine (50 ml), dried (magnesium sulphate) filteredand evaporated. The residue was purified by subjecting to chromatographyon silica gel using ethyl acetate:hexane (75:25) as eluant. There wasthus obtained methyl 4-3-(2-benzyloxy-5-(carbamoylmethoxy)phenyl)propyl!benzoate (200 mg).

EXAMPLE 7

4- 3-(2-Benzyloxy-5-methylthiophenyl)!benzoic acid

(A) Methyl 4- 3-(2-benzyloxy-5-methylthiophenyl)-propyl!benzoate wasconverted to 4- 3-(2-benzyloxy-5-methylthiophenyl)propyl!benzoic acidmp.: 110°-112° C., using the method described in Example 1 for theconversion of methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)-propyl!benzoic acid except that the product waspurified by crystallisation from methanol instead of chromatography.

Methyl 4- 3-(2-benzyloxy-5-methylthiophenyl)propyl!benzoate was preparedfrom 4-methylmercaptophenol as follows:

(B) To a mixture of 4-methylmercaptophenol (50 g) in trifluoroaceticacid (260 ml) was added hexamine (50 g) in small portions at below 50°C. The mixture was heated at 100° C. for 2 hours, cooled and 50%sulphuric acid (1 l) was added. The mixture was stirred for 1 hour,extracted with diethyl ether (4×200 ml), the combined extracts dried(magnesium sulphate) and evaporated. The residue was purified bysubjecting to chromatography on silica gel using dichloromethane:hexane(3:2) as eluant. There was thus obtained5-methylthio-2-hydroxybenzaldehyde (5.2 g).

(C) A mixture of 5-methylthio-2-hydroxybenzaldehyde (5.2 g), benzylbromide (5.3 g), potassium carbonate (12.8 g) in acetone was heated atreflux for 4 hours, cooled, filtered and evaporated. The residue waspurified by subjecting to chromatography on silica gel usingdichloromethane:hexane (7:3) as eluant. There was thus obtained5-methylthio-2-benzyloxybenzaldehyde (5.2 g).

(D) 5-Methylthio-2-benzyloxybenzaldehyde was converted to methyl 4-3-(2-benzyloxy-5-methylthiophenyl)propenyl!benzoate (as a mixture ofdouble bond isomers) by the first 2 stages of the method described inExample 1 as the second alternative method to synthesise methyl 4-3-(2-hydroxyphenyl)propyl!benzoate except that in the second step toform the methyl ester sulphuric acid was used in place of thionylchloride.

(E) A mixture of methyl 4-3-(2-benzyloxy-5-methylthiophenyl)propenyl!benzoate (as a mixture ofdouble bond isomers) (3.3 g) and Wilkinson's catalyst (330 mg) wasstirred at 50° C. under 50 atm. of hydrogen for 18 hours. The solventwas evaporated and the residue was purified by subjecting tochromatography on silica gel using dichloromethane:hexane (4:1) aseluant. There was thus obtained methyl 4-3-(2-benzyloxy-5-methylthiophenyl)propyl!benzoate (3.1 g).

EXAMPLE 8

4- 2-Benzyloxyphenethyl!-3-fluorobenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)ethyl)-3-fluorobenzoate was convertedto 4- 2-(2-benzyloxyphenyl)ethyl!-3-fluorobenzoic acid mp. 141°-142° C.,using the method described in Example 1 for the conversion of methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid.

Methyl 4- 2-(2-benzyloxyphenyl)ethyl)-3-fluorobenzoate was prepared asfollows:

(B) Methyl 3-fluoro-4-methylbenzoate was prepared from3-fluoro-4-methylbenzoic acid by the process described in Example 6 forthe synthesis of methyl4-(3-(2-benzyloxy-5-hydroxyphenyl)propyl!-benzoate.

(C) A mixture of methyl 3-fluoro-4-methylbenzoate (4.3 g),N-bromosuccinimide (4.5 g) and AIBN (20 mg) in carbon tetrachloride wasirradiated with a 100 W Tungsten lamp at reflux for 1 hour. The mixturewas filtered through diatomaceous earth, and evaporated to give methyl3-fluoro-4-(bromomethyl)benzoate (5.0 g).

(D) A mixture of methyl 3-fluoro-4-(bromomethyl)benzoate (4.0 g) andtriphenylphosphine (5.4 g) in toluene (100 ml) was heated at reflux for18 hours and filtered. The filtered solid was washed with toluene anddried. There was thus obtained(4-carboxymethyl-2-fluorophenyl)methyltriphenylphosphonium bromide (5.6g).

(E) To a mixture of(4-carboxymethyl-2-fluorophenyl)methyltriphenylphosphonium bromide (5.5g) in THF (100 ml) at 0° C. was added lithium hexamethyldisilazide (11.9ml, 1.0M solution in THF). After 1 hour a solution of2-benzyloxybenzaldehyde (commercially available, or prepared fromsalicylaldehyde and benzyl bromide using the method described above tosynthesise 4- 3-(2-hydroxyphenyl)propyl!benzoate) (4.0 g) in THF (10 ml)was added and the mixture stirred for 2 hours. The mixture was pouredinto ethyl acetate (100 ml) and 1N HCl (100 ml), the layers separatedand the organic solution washed with sodium bicarbonate (100 ml) andbrine (100 ml), dried (magnesium sulphate), filtered and evaporated. Theresidue was purified by chromatography on silica gel using ethylacetate:hexane (1:9) as eluant. There was thus obtained methyl 4-2-(2-benzyloxyphenyl)-ethenyl!-3-fluorobenzoate (3.7 g).

(F) Methyl 4- 2-(2-hydroxyphenyl)ethyl!-3-fluorobenzoate was synthesisedfrom methyl 4-(2-(2-benzyloxyphenyl) ethenyl!-3-fluorobenzoate using thehydrogenation method described in Example 1 (for the conversion of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!-benzoate to methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl)benzoate but using ethanol as thereaction solvent).

(G) Methyl 4-(2-(2-benzyloxyphenyl)ethyl!-3-fluorobenzoate was preparedfrom methyl 4- 2-(2-hydroxyphenyl)ethyl!-3-fluorobenzoate using themethod described in Example 1 for the synthesis of methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate.

EXAMPLE 9

4- 2-Benzyloxyphenethyl!-3-aminobenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)ethyl!-3-aminobenzoate was convertedto 4- 2-(2-benzyloxyphenyl)ethyl!-3-aminobenzoic acid hydrochloride mp.227°-229° C., using the method described in Example 1 for the conversionof methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl! benzoic acid except that the residue waspurified by washing with 1M HCl and triturating with diethyl etherinstead of by subjecting to chromatography.

(B) Methyl 4- 2-(2-benzyloxyphenyl)ethyl!-3-aminobenzoate was preparedas follows:

(C) Methyl 4- 2-(2-benzyloxyphenyl)ethenyl!-3-nitrobenzoate was preparedfrom 3-nitro-4-methylbenzoic acid using the methods described in Example8 for the conversion of 3-fluoro-4-methylbenzoic acid to methyl 4-2-(2-benzyloxyphenyl)ethenyl!-3-fluorobenzoate.

(D) A mixture of methyl 4- 2-(2-benzyloxyphenyl)ethenyl)-3-nitrobenzoate(2.5 g) and 5% Rhodium on alumina (520 mg) in ethanol (200 ml) wasstirred under 1 atm. of hydrogen for 20 hours. The mixture was filteredand the solvent evaporated. The residue was purified by subjecting tochromatography using ethylacetate: dichloromethane (9:1) as eluant.There was thus obtained methyl 4-2-(2-benzyloxyphenyl)ethyl!-3-aminobenzoate (1.71 g).

EXAMPLE 10

4- 2-(2-Benzyloxyphenyl)-(E)-ethenyl!-2-hydroxybenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-hydroxybenzoate wasconverted to 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-hydroxybenzoic acidmp. 214°-216° C., using the method described in Example 1 for theconversion of methyl 4- 3-(2-benzyloxyphenyl)propyl)benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom dichloromethane/hexane rather than by subjecting to chromatography.

(B) Methyl 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-hydroxy-benzoate wasprepared as follows:

(C) Methyl 2-hydroxy-4-methylbenzoate was prepared from2-hydroxy-4-methylbenzoic acid by the process described in Example 6 forthe synthesis of methyl4-(3-(2-benzyloxy-5-hydroxyphenyl)propyl!-benzoate.

(D) A mixture of methyl 2-hydroxy-4-methylbenzoate (7.19 g), aceticanhydride (25 ml) and pyridine (25 ml) was stirred for 18 hours,filtered and evaporated. There was thus obtained methyl2-acetoxy-4-methylbenzoate (9.0 g).

(E) Methyl 2-acetoxy-4-methylbenzoate was converted to a mixture ofmethyl 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-hydroxybenzoate andmethyl 4- 2-(2-benzyloxyphenyl)-(Z)-ethenyl!-2-hydroxybenzoate using theprocedures described in Example 8 for the synthesis of methyl 4-2-(2-benzyloxyphenyl)ethenyl)-3-fluorobenzoate from methyl3-fluoro-4-methylbenzoate (using 2 equivalents of lithiumhexamethyldisilazide in the final step). The isomers were separated bysubjecting to chromatography on silica gel using adichloromethane:hexane (1:2) as eluant. Further purification of theisomers was achieved by crystallisation.

EXAMPLE 11

4- 2- 2-Benzyloxyphenyl)-(Z)-ethyl!-2-hydroxybenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)-(Z)-ethenyl!-2-hydroxy-benzoate(synthesised as described in Example 12) was converted to 4-2-2-benzyloxyphenyl)-(Z)-ethenyl!-2-hydroxybenzoic acid mp. 113°-114°C., using the method described in Example 1 for the conversion of methyl4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom diethyl ether/hexane rather than by subjecting to chromatography.

EXAMPLE 12

4- 2-(2-Benzyloxyphenyl)-(E)-ethyenyl!-2-methoxybenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl)-2-methoxybenzoate wasconverted to 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-methoxybenzoic acidmp. 154°-156° C., using the method described in Example 1 for theconversion of methyl 4- 3-(2-benzyloxyphenyl)propyl)benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom dichloromethane/ethyl acetate rather than by subjecting tochromatography.

Methyl 4- 2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-methoxybenzoate wassynthesised as follows:

(B) A mixture of methyl 4-2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-hydroxybenzoate (synthesised asdescribed in Example 10) (0.5 g), methyl iodide (0.5 ml) and potassiumcarbonate (0.5 g) in DMF (10 ml) was stirred for 18 hours, poured intowater (100 ml) and ethyl acetate (100 ml), the layers separated and theorganic layer washed with brine and dried (magnesium sulphate). Therewas thus obtained methyl 4-2-(2-benzyloxyphenyl)-E-ethenyl!-2-methoxybenzoate (0.52 g).

EXAMPLE 13

4- 2-(2-Benzyloxyphenyl)-(Z)-ethenyl!-2-methoxybenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)-(Z)-ethenyl!-2-methoxy-benzoate(obtained from methyl 4-2-(2-benzyloxyphenyl)-(Z)-ethenyl!-2-hydroxybenzoate as described inExample 14) was converted to 4-2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-methoxybenzoic acid (containing 15%of the (Z) isomer and obtained as a gum; negative FAB mass peak 359)using the method described in Example 1 for the conversion of methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)-propyl!benzoic acid.

EXAMPLE 14

4- 2-Benzyloxyphenethyl!-2-hydroxybenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)ethyl!-2-hydroxybenzoate wasconverted to 4- 2-(2-benzyloxyphenyl)ethyl!-2-hydroxybenzoic acid mp.184°-186° C., using the method described in Example 1 for the conversionof methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to4-(3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom diethyl ether/hexane rather than by subjecting to chromatography.

(B) Methyl 4- 2-(2-benzyloxyphenyl)ethyl!-2-hydroxybenzoate was preparedfrom a Z/E mixture of methyl 4-2-(2-benzyloxyphenyl)-ethenyl!-2-hydroxybenzoate (prepared as describedin Example 10) using the hydrogenation method described in Example 10for the synthesis of methyl 4-2-(2-benzyloxyphenyl)ethyl!-3-aminobenzoate.

EXAMPLE 15

4- 2-Benzyloxyphenethyl!-2-methoxybenzoic acid

(A) Methyl 4- 2-(2-benzyloxyphenyl)ethyl!-2-methoxybenzoate wasconverted to 4- 2-(2-benzyloxyphenyl)ethyl!-2-methoxybenzoic acid mp.124°-125° C., using the method described in Example 1 for the conversionof methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom dichloromethane/hexane rather than by subjecting to chromatography.

(B) Methyl 4- 2-(2-benzyloxyphenyl)ethyl!-2-methoxybenzoate was preparedfrom methyl 4- 2-(2-benzyloxyphenyl)ethyl!-2-hydroxybenzoate (preparedas described in Example 14) using the method described in Example 14 forthe preparation of methyl 4-2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-methoxybenzoate.

EXAMPLE 16

4- 3-(2-Benzyloxyphenyl)propyl!-2-hydroxybenzoic acid

(A) Methyl 4-(3-(2-benzyloxyphenyl)propyl!-2-hydroxybenzoate wasconverted to 4-(3-(2-benzyloxyphenyl)propyl!-2-hydroxybenzoic acid mp.130°-131° C., using the method described in Example 1 for the conversionof methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom diethyl ether/hexane rather than by subjecting to chromatography.

Methyl 4- 3-(2-benzyloxyphenyl)propyl!-2-hydroxybenzoate was prepared asfollows:

(B) Methyl 4- 3-(2-benzyloxyphenyl)propenyl!-2-hydroxybenzoate (as amixture of double bond regio and stereoisomers) was prepared by themethods described in Example 12 for the synthesis of the E/Z mixture ofmethyl 4- 2-(2-benzyloxyphenyl;ethenyl!-2-hydroxybenzoates using(2-benzyloxyphenyl)acetaldehyde in place of 2-benzyloxybenzaldehyde.

(C) Methyl 4- 3-(2-benzyloxyphenyl)propyl!-2-hydroxybenzoate wasprepared from methyl 4- 3-(2-benzyloxyphenyl)propenyl!-2-hydroxybenzoateby the method described in Example 9 for the synthesis of methyl 4-2-(2-benzyloxyphenyl)ethyl!-3-aminobenzoate from methyl 4-2-(2-benzyloxyphenyl)ethenyl!-3-nitrobenzoate.

EXAMPLE 17

4- 3-(2-Benzyloxyphenyl)propyl!-2-methoxybenzoic acid

(A) Methyl 4- 3-(2-benzyloxyphenyl)propyl!2-methoxybenzoate wasconverted to 4- 3-(2-benzyloxyphenyl)propyl!-2-methoxybenzoic acid mp.60°-62° C., using the method described in Example 1 for the conversionof methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid purifying by crystallisationfrom diethyl ether/hexane rather than by subjecting to chromatography.

(B) Methyl 4- 3-(2-benzyloxyphenyl)-propyl!-2-methoxybenzoate wassynthesised from methyl 4-3-(2-benzyloxyphenyl)-propyl!-2-hydroxybenzoate (prepared as describedin Example 15) as described in Example 14 for the synthesis of methyl 4-2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-methoxybenzoate from methyl 4-2-(2-benzyloxyphenyl)-(E)-ethenyl!-2-hydroxybenzoate.

EXAMPLE 18

4- 3-(2-(1-Phenethyloxy)phenyl)propyl!benzoic acid

(A) 4- 3-(2-(1-Phenethyloxy)phenyl)propenyl!benzoic acid as a mixture ofdouble bond isomers was hydrogenated under the conditions described inExample 1 (for the conversion of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)propenyl!benzoate to methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl!benzoate) ensuring that only oneequivalent of hydrogen was taken up. There was thus obtained 4-3-(2-(1-phenethyloxy)phenyl)propyl!benzoic acid mp. 103°-104° C.

4- 3-(2-(1-Phenethyloxy)phenyl)propenyl!benzoic acid was synthesised asfollows:

(B) Salicylaldehyde and 1-bromo-1-phenylethane were converted to2-(1-phenethyloxy)benzaldehyde using the process described in Example 1for the conversion of 4- 3-(2-hydroxyphenyl)propyl)benzoate to methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate except that the reaction mixturewas heated at 120° C. for 23 hours.

(C) 2-(1-Phenethyloxy)benzaldehyde was converted to 4-3-(2-(1-phenethyloxy)phenyl)propenyl!benzoic acid (as a mixture ofdouble bond isomers) by the first stage of the method described inExample 1 as the second alternative method to synthesise methyl 4-3-(2-hydroxyphenyl)propyl!benzoate.

EXAMPLE 19

3- 3-(2-Benzyloxyphenyl)propyl!benzoic acid

(A) Methyl 3- 3-(2-benzyloxyphenyl)propyl)benzoate was converted to 3-3-(2-benzyloxyphenyl)propyl!benzoic acid mp. 88°-90° C., using themethod described in Example 1 for the conversion of methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid.

Methyl 3- 3-(2-benzyloxyphenyl)propyl!benzoate was prepared as follows:

(B) 1-Allyl-2-benzyloxybenzene was obtained from 2-allylphenol by thebenzylation procedure described in Example 1 for the conversion of 4-3-(2-hydroxyphenyl)propyl!benzoate to methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate.

(C) A mixture of 1-allyl-2-benzyloxybenzene (0.54 g), methyl3-iodobenzoate (0.5 g), bistriphenylphosphine palladium dichloride (30mg) and CuI (4 mg) in degassed triethylamine (25 ml) was heated at 60°C. for 18 hours. The solvent was evaporated and the residue dissolved indichloromethane and washed with 1M HCl (2×20 ml) and brine (25 ml). Theorganic solution was evaporated and the residue purified by subjectingto chromatography on silica gel using ethyl acetate:hexane (8:92) aseluant. There was thus obtained methyl 3-3-(2-benzyloxyphenyl)propenyl)benzoate (0.4 g).

(D) Methyl 3- 3-(2-benzyloxyphenyl)propenyl!benzoate was hydrogenatedunder the conditions described in Example 1 (for the conversion of4-(3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!-benzoate to methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl)benzoate) using ethanol as thereaction solvent to give methyl 3- 3-(2-hydroxyphenyl)propylibenzoate.

(E) Methyl 3-(3-(2-benzyloxyphenyl)propyl!benzoate was prepared frommethyl 3-(3-(2-hydroxyphenyl)propyl!benzoate using the method describedin Example 1 for the synthesis of methyl 4-3-(2-benzyloxyphenyl)propyl)benzoate.

EXAMPLE 20

5-{4- 2(2-Benzyloxyphenyl)ethenyl!phenyl}tetrazole

(A) 2-(Pivaloyloxymethyl)-5-{2-(2-benzyloxyphenyl)ethenyl!-4-phenyl}tetrazole was converted to 5-{4-2-(2-benzyloxyphenyl)ethenyl!phenyl} tetrazole as a 55:45 mixture of E:Zisomers mp. 176°-177° C., using the method described in Example 1 forthe conversion of methyl 4- 3-(2-benzyloxyphenyl)-propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid.

2-(Pivaloyloxymethyl)-5-{2-(2-benzyloxyphenyl)ethenyl!-4-phenyl}-tetrazole was obtained asfollows:

(B) 4- 2-(2-Benzyloxyphenyl)ethenyl!benzonitrile as a mixture of isomerswas synthesised from 2-benzyloxybenzaldehyde using the method describedin Example 8 for the conversion of 2-benzyloxybenzaldehyde to methyl 4-2-(2-benzyloxyphenyl)ethenyl!-3-fluorobenzoate using(4-cyanophenyl)methyltriphenylphosphonium bromide in place of(4-methoxycarbonyl-2-fluorophenyl)methyltriphenylphosphonium bromide.

(C) A mixture of 4- 2-(2-benzyloxyphenyl)ethenyl!-benzonitrile as amixture of isomers (7.88 g) and tri-n-butyltin azide (20.03 ml, 2.53Msolution in toluene) in toluene 100 ml was heated at reflux for 66hours. The mixture was cooled (ice bath) and added dropwise to excesssodium nitrite and stirred for 30 minutes. Sulphamic acid (9 g) wasadded and the mixture left to stand at 5° C. for 18 hours. The resultingyellow precipitate (9.7 g) was filtered off, dried and mixed withpotassium carbonate (7.56 g) in DMF (20 ml) and stirred for 10 minutes.Pivaloyloxymethyl chloride (4.78 ml) was added to the mixture and it wasstirred for 18 hours, diluted with ethyl acetate (200 ml), and washedwith 1M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml),dried (magnesium sulphate), filtered and evaporated. The residue waspurified by subjecting to chromatography on silica gel using methanol :dichloromethane (0:100 to 30:70 gradient) as eluant. There was thusobtained N-2-(pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)ethenyl!-phenyl}tetrazole (7.64 g) andN-1-(pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)ethenyl!-phenyl}tetrazole (1.67 g).

EXAMPLE 21

2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)-ethyl!phenyl}tetrazole

2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)-ethenyl!phenyl}tetrazole (synthesised as describedin Example 20) was converted to 2-(pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)-ethyl!phenyl}tetrazole by the process described inExample 1 (for the conversion of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!-benzoate to methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl!benzoate) ensuring that only oneequivalent of hydrogen was taken up.

EXAMPLE 22

5-{4- 2-Benzyloxyphenyl)ethyl!-phenyl}tetrazole

2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)ethyl!-phenyl}tetrazole was converted to 5-{-4-2-(2-benzyloxyphenyl)ethyl!-phenyl}tetrazole (mp. 223°-225° C.) usingthe method described in Example 1 for the conversion of methyl4-(3-(2-benzyloxyphenyl)-propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid.

EXAMPLE 23

5-{-4- 2-(2-Benzyloxy-5-acetylphenyl)ethyl!phenyl}tetrazole

(A) 2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxy-5-acetylphenyl)ethyl!phenyl}tetrazole was converted to5-{-4- 2-(2-benzyloxy-5-acetylphenyl)ethyl!phenyl}tetrazole mp.193°-195° C., using the method described in Example 1 for the conversionof methyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl)- benzoic acid.

2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxy-5-acetyl-phenyl)ethyl!phenyl}tetrazole was obtained asfollows:

(B) 2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)-ethenyl!phenyl}tetrazole (obtained as described inExample 20) was converted to 2-(pivaloyloxymethyl)-5-{-4-2-(2-hydroxyphenyl)-ethyl!phenyl}tetrazole by the process described inExample 1 (for the conversion of 4-3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!-benzoate to methyl 4-3-(2-hydroxyphenyl)-3-carbonylpropyl!benzoate)

(C) 2-(Pivaloyloxymethyl)-5-{-4-2-(2-hydroxyphenyl)ethyl!-phenyl}tetrazole was converted to2-(pivaloyloxymethyl)-5-{-4-2-(2-hydroxy-5-acetylphenyl)ethyl!phenyl}tetrazole by the methoddescribed in example 3, footnote j, for the conversion of methyl4-!3-(2-hydroxyphenyl)propyl!benzoate to methyl4-(3-(2-hydroxy-5-acetylphenyl)propyl!benzoate.

(D) 2-(Pivaloyloxymethyl)-5-{-4-2-(2-hydroxy-5-acetylphenyl)ethyl!phenyl}tetrazole was converted toN-2-(pivaloyloxymethyl)-5-{-4--2-(2-benzyloxy-5-acetylphenyl)ethyl!phenyl}tetrazole by the process described in Example 1 for theconversion of 4- 3-(2-hydroxyphenyl)propyl!benzoate to methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate.

EXAMPLE 24

5-{4- 2-(2-Benzyloxy-5-bromo-phenyl)ethyl!phenyl}tetrazole

(A) 2-(Pivaloyloxymethyl)-5-{(-4-2-(2-benzyloxy-5-bromophenyl)ethyl!phenyl}tetrazole was converted to5-{-4- 2-(2-benzyloxy-5-bromophenyl)ethyl!phenyl}tetrazole mp. 256°-258°C., using the method described in Example 1 for the conversion of methyl4- 3-(2-benzyloxyphenyl)propyl!benzoate to 4-3-(2-benzyloxyphenyl)-propyl!benzoic acid.

2-(Pivaloyloxymethyl)-5-{-4-2-(2-benzyloxy-5-bromophenyl)-ethyl!phenyl}-tetrazole was obtained asfollows:

(B) 2-(Pivaloyloxymethyl)-5-{-4-2-(2-hydroxyphenyl)ethyl!-phenyl}tetrazole (prepared as described inExample 23) was converted to N-2-(pivaloyloxymethyl)-5-{-4-2-(2-hydroxy-5-bromophenyl)ethyl!-phenyl}tetrazole by the methoddescribed in example 3, footnote m, for the conversion of methyl 4-3-(2-hydroxyphenyl)propyl!benzoate to methyl 4-3-(2-hydroxy-5-bromophenyl)propyl!benzoate.

(C) 2-(Pivaloyloxymethyl)-5-{-4- 2-(2-hydroxy-5-bromophenyl)ethyl!phenyltetrazole was converted to N-2-(pivaloyloxymethyl)-5-{-4-2-(2-benzyloxy-5-bromophenyl)ethyl!-phenyl}tetrazole by the processdescribed in Example 1 for the conversion of 4-3-(2-hydroxyphenyl)propyl!benzoate to methyl 4-3-(2-benzyloxyphenyl)propyl!benzoate.

EXAMPLE 25

5-{-4- 3-(2-Benzyloxyphenyl)-propyl!phenyl}tetrazole

(A) 2-(Pivaloyloxymethyl)-5-{-4-3-(2-benzyloxyphenyl)-propyl!phenyl}tetrazole was converted to 5-{-4-3-(2-benzyloxyphenyl)-propyl3phenyl}tetrazole mp. 185.5°-186.5° C. usingthe method described in Example 1 for the conversion of methyl 4-3-(2-benzyloxyphenyl)-propyl!benzoate to 4-3-(2-benzyloxyphenyl)propyl!benzoic acid.

2-(Pivaloyloxymethyl)-5-{-4-3-(2-benzyloxyphenyl)propyl!-phenyl}tetrazole was obtained-as follows:

(B) To a mixture of 2-(4-cyanophenyl)ethanol (5 g) in diethyl ether wasadded phosphorus tribromide (3.94 ml) dropwise. The mixture was heatedat reflux for 3 hours, poured into water (200 ml) and the organic layerwashed with sodium bicarbonate (100 ml) and brine (100 ml), dried(magnesium sulphate), filtered and evaporated. There was thus obtained(4-cyanophenethyl)bromide (3.34 g).

(C) A mixture of (4-cyanophenethyl)bromide (3.24 g) andtriphenylphosphine (8.06 g) in toluene was heated at reflux for 72hours. The suspension was filtered off and washed with toluene. Theresulting solid was triturated with diethyl ether. There was thusobtained 2-(4-cyanophenyl)ethyltriphenylphosphonium bromide (5.7 g).

(D) 2-(4-Cyanophenyl)ethyltriphenylphosphonium bromide was converted to2-(4-tetrazol-5-ylphenyl)ethyltriphenylphosphonium chloride using themethod described in Example 20 for the conversion of 4-2-(2-benzyloxyphenyl)ethenyl!benzonitrile to crude 5-{-4-2-(2-benzyloxyphenyl)ethenyl!phenyl}tetrazole.

(E) 2-(4-Tetrazol-5-ylphenyl)ethyltriphenylphosphonium chloride and2-benzyloxybenzaldehyde were converted to 5-{-4-(3-(2-benzyloxyphenyl)propenyl!phenyl}tetrazole as a mixture of doublebond isomers using the first stage of the method described in Example 1as the second alternative method to synthesise methyl 4-3-(2-hydroxyphenyl) propyl!benzoate.

(F) 5-{-4- 3-(2-Benzyloxyphenyl)propenyl!phenyl}tetrazole as a mixtureof double bond isomers was converted to 2-(pivaloyloxymethyl)-5-{-4-3-(2-benzyloxyphenyl)propenyl!phenyl}-tetrazole by the method describedin Example 19 for the synthesis of 2-(pivaloyloxymethyl)-5-{-4-2-(2-benzyloxyphenyl)ethenyl!phenyl}-tetrazole.

(G) 2-(Pivaloyloxymethyl)-5-{-4-3-(2-benzyloxyphenyl)-propenyl!-4-phenyl}tetrazole was converted to2-(pivaloyloxymethyl)-5-{-4- 3-(2-hydroxyphenyl)propyl!phenyl}-tetrazoleby the process described in Example 1 (for the conversion of4-(3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl!benzoate to methyl 4-3-(7-hydroxyphenyl)-3-carbonylpropyl!benzoate).

(H) 2-(Pivaloyloxymethyl)-5-{-4-3-(2-hydroxyphenyl)propyl!-phenyl}tetrazole was converted to2-(pivaloyloxymethyl)-5-{-4-3-(2-benzyloxyphenyl)propyl!phenyl}tetrazole by the process described inExample 1 for the conversion of 4- 3-(2-hydroxyphenyl)propyl!benzoate tomethyl 4- 3-(2-benzyloxyphenyl)propyl!benzoate.

EXAMPLE 26

4- 4-(2-Benzyloxyphenyl)butyl!benzoic acid

(A) 4- 4-(2-benzyloxyphenyl)butyl!benzoic acid (mpt.105° C.) wasprepared using a similar process to that described in Example 1 (A) fromthe corresponding methyl ester.

(B) Methyl 4- 4-(2-benzyloxyphenyl)butyl!benzoate was obtained asfollows: benzyl 2-benzyloxyphenylacetate was obtained from2-hydroxyphenylacetic acid using a similar method to that of Example 1(I) except that two equivalents of benzyl bromide were used.

(C) To a solution of benzyl 2-benzyloxyphenylacetate (3.32 g) in CH₂ Cl₂(35 ml) at -70° C. was added a 1M solution of DIBAL in CH₂ Cl₂ (12 ml).The reaction was stirred at -70° C. for 1.5 hours washed with 2N HCl,water, saturated aqueous sodium hydrogen carbonate solution and brine.The solution was dried (MgSO₄) and evaporated. The residue was purifiedby chromatography on silica gel using CH₂ Cl₂ as eluant. There was thusobtained 2-benzyloxyphenylacetaldehyde (1.68 g).

(D) 4- 4-(2-benzyloxyphenyl)but-2-enyl!benzoate was obtained from2-benzyloxyphenylacetaldehyde and 1-{4-carboxyphenyl)ethyltriphenylphosphonium bromide (see Example 1 (G)) using a similar methodto that of Example 8 (E).

(E) 4- 4-(2-benzyloxyphenyl)butyl!benzoic acid was obtained from 4-4-(2-benzyloxyphenyl)but2-enyl!benzoate using a similar method to thatof Example 7 (E).

EXAMPLE 27

2- 3-(2-Benzyloxyphenyl)propyl!thiazol-4-ylcarboxylic acid

A similar process to that described in Example 1 (A) but using ethyl 2-3-(2-benzyloxyphenyl)propyl!thiazol-4-ylcarboxylate was used to give thetitle compound (mpt. 93°-96° C.). Ethyl 4-3-(2-benzyloxyphenyl)propyl!thiazol-2-ylcarboxylate was obtained from2-benzyloxyphenylacetaldehyde and4-ethoxycarbonylthiazol-2-ylmethyltriphenylphosphonium bromide using asimilar method to that of Example 8 (E) (the pendant benzyloxy groupremained attached).

The "phosphonium bromide" was obtained from ethyl2-methylthiazol-4-ylcarboxylate using similar methods to those ofExample 8 (C) and Example 8 (D).

EXAMPLE 28

A similar process to that of Example 1(A) with the appropriate methylbenzoates was used to prepare the compounds in the following table withappropriate modifications described in the footnotes.

    __________________________________________________________________________     ##STR28##                                                                    Compound                                                                            R.sup.1                                                                            Link   Ar      mpt     Footnote                                    __________________________________________________________________________    1     5-Br CH.sub.2 CH.sub.2                                                                     ##STR29##                                                                            208-209 a                                           2     5-Br CH.sub.2 CH.sub.2                                                                     ##STR30##                                                                            143-144 b                                           3     5-SMe                                                                              (E)CHCH                                                                              "       174-176 c                                           4     5-SMe                                                                              (E)CHCH                                                                               ##STR31##                                                                            241-244 d                                           5     5-SMe                                                                              CH.sub.2 CH.sub.2                                                                    "       190-191 e                                           6     5-SMe                                                                              CH.sub.2 CH.sub.2                                                                     ##STR32##                                                                            134-135 f                                           7     5-SO.sub.2 Me                                                                      CH.sub.2 CH2                                                                          ##STR33##                                                                            230-232 g                                           8     5-OMe                                                                              (E)CHCH                                                                              "       211-212 h                                           9     5-OMe                                                                              CH.sub.2 CH.sub.2                                                                    "       162-163 i                                           10    5-CH.sub.3                                                                         CH.sub.2 CH.sub.2                                                                    "       190-191 j                                           11    H    CH.sub.2 CH.sub.2                                                                     ##STR34##                                                                            115-116 k                                           12    H    (CH.sub.2).sub.3                                                                      ##STR35##                                                                            --      l                                           13    H    (E) (CHCH)                                                                            ##STR36##                                                                            205-207 m                                           14    H    (CH.sub.2).sub.2                                                                     "       167-170 n                                           15    H    (CH.sub.2).sub.3                                                                     "       --      o                                           16    H    (E) (CHCH)                                                                            ##STR37##                                                                            87-89   p                                           17    H    (CH.sub.2).sub.3                                                                      ##STR38##                                                                            60-63   q                                           18    H    (CH.sub.2).sub.3                                                                      ##STR39##                                                                            --      r                                           19    H    (E)CHCH                                                                               ##STR40##                                                                            174     s                                           20    5-Br (E)CHCH                                                                               ##STR41##                                                                            194-200 t                                           21    5-Br CH.sub.2 CH.sub.2                                                                    "       196-199 u                                           22    H    CH.sub.2 CH.sub.2                                                                     ##STR42##                                                                            --      v                                           23    5-SMe                                                                              (E)CHCH                                                                               ##STR43##                                                                            200-206 w                                           24    5-SO.sub.2 Me                                                                      (E)CHCH                                                                              "       196-200 x                                           25    6-OH (CH.sub.2).sub.3                                                                      ##STR44##                                                                            144-146 y                                           26    6-OCH.sub.2 Ph                                                                     (CH.sub.2).sub.3                                                                     "       142-143                                             27    6-OMe                                                                              (CH.sub.2).sub.3                                                                     "       166-167 z                                           28    5-SMe                                                                              (CH.sub.2).sub.2                                                                      ##STR45##                                                                            151-154 (aa)                                        29    5-SO.sub.2 Me                                                                      (CH.sub.2).sub.2                                                                     "       190-192 (ab)                                        30    5-SO.sub.2 Me                                                                      (CH.sub.2).sub.2                                                                      ##STR46##                                                                            206-210 (ab)                                        31    H    (E) (CHCH)                                                                            ##STR47##                                                                            160-161.5                                                                             (ac)                                        32    H    (E)CHCH                                                                               ##STR48##                                                                            181-182 (ad)                                        33    H    (CH.sub.2).sub.2                                                                      ##STR49##                                                                            170-171 (ae)                                        34    H    (CH.sub.2).sub.2                                                                      ##STR50##                                                                            131-131.5                                                                             (af)                                        35    H    (Z) (CHCH)                                                                            ##STR51##                                                                            140-144 (ag)                                        36    H    (CH.sub.2).sub.2                                                                      ##STR52##                                                                            165.5-166.5                                                                           (ah)                                        37    H    (CH.sub.2).sub.2                                                                      ##STR53##                                                                            151.5-152.5|                                                                 (ai)                                        38    H    (CH.sub.2).sub.2                                                                      ##STR54##                                                                            186-187 (aj)                                        39    H    (CH.sub.2).sub.2                                                                      ##STR55##                                                                            187.5-188                                                                             (ak)                                        40    H    (CH.sub.2).sub.3                                                                      ##STR56##                                                                            105-106.5                                                                             (al)                                        41    H    (CH.sub.2).sub.3                                                                      ##STR57##                                                                            123-124 (am)                                        42    H    (E)CHCH                                                                               ##STR58##                                                                            214-215 (an)                                        43    H    (CH.sub.2).sub.2                                                                     "       203-204 (ao)                                        44    H    (CH.sub.2).sub.3                                                                      ##STR59##                                                                            121.5-122                                                                             (ap)                                        45    5-Cl (Z)CHCH                                                                              "       191.5-192                                                                             (aq)                                        46    5-Cl (E)CHCH                                                                              "       216.5-217                                                                             (aq)                                        47    5-Cl (CH.sub.2).sub.2                                                                     "       158.5-159.5                                                                           (ar)                                        48    5-Br (CH.sub.2).sub.2                                                                      ##STR60##                                                                            250-252                                             49    H    (CH.sub.2).sub.2                                                                      ##STR61##                                                                            215.5-216.5                                                                           (as)                                        __________________________________________________________________________     Footnotes                                                                     a: Methyl 4(2-(benzyloxy-5-bromophenethyl)-2-hydroxybenzoate was prepared     from a Z/E mixture of methyl                                                  4 2-(2-benzyloxy-5-bromo-phenyl)ethenyl!-2-hydroxybenzoate using a simila     method to that of Example 7 (E). The alkenes were prepared from               2benzyloxy-5-bromobenzaldehyde and                                            4methoxycarbonyl-3-acetoxybenzyl-triphenylphosphonuim bromide by a simila     method to that of Example 8 (E) in the course of which the acetate group      was hydrolysed.                                                               b: Methyl 4(2-benzyloxy-5-bromophenethyl)-2-methoxybenzoate was prepared      from methyl 4(2-benzyloxy-5-bromophenethyl)-2-hydroxybenzoate using a         similar method to that of Example 2, Footnote C (A) replacing allyl           bromide with methyl iodide.                                                   c: Methyl 4{2-(2-benzyloxy-5-methanethiophenyl) ethenyl!-2methoxybenzoate     was prepared from methyl                                                      4 2-(2-benzyloxy-5-methanethiophenyl)ethenyl!-2-hydroxybenzoate using a       similar method to that of Example 2, Footnote C (A) replacing allyl           bromide with methyl iodide.                                                   Methyl 4 2-(2-benzyloxy-5-methanethiophenyl) ethenyl!-2hydroxybenzoate wa     prepared from 2benzyloxy-4-methanethio-benzaldehyde and                       4methoxycarbonyl-3-acetoxybenzyltriphenylphosphonium bromide using a          similar method to that of Example 8, (E) in the course of which the           acetate group was hydrolysed. The required E isomer was obtained from the     mixture of Z and E isomers by separation using MPLC on silica gel.            d: See second part of note (c).                                               e: Methyl 4 2-benzyloxy-5-methanethiophenethyl)-2-hydroxybenzoate was         prepared from the corresponding alkenes using a similar method of that of     Example 7, (E).                                                               f: Methyl 4 2-benzyloxy-5-methanethiophenethyl)-2-methoxybenzoate was         prepared from methyl                                                          4 2-benzyloxy-5-methanethiophenethyl)-2-hydroxybenzoate using a similar       method to that a Example 2, Footnote c, (A) replacing allyl bromide with      methyl iodide.                                                                g: Methyl 4 2-benzyloxy-5-methanesulphonylphenethyl!-2-hydroxybenzoate wa     prepared from the corresponding sulphide using a modification of the          method of Example 49, in which the reaction was carried out at 0°      C.                                                                            h: Methyl 4 2-(2-benzyloxy-5-methoxyphenyl) ethenyl!-2hydroxybenzoate was     prepared by the second part of the method described in Footnote (c) using     2benzyloxy-5-methoxybenzaldehyde in place of                                  2benzyloxy-5-methylthiobenzaldehyde.                                          i: Methyl 4(2-benzyloxy-5-methoxyphenethyl)-2-hydroxybenzoate was prepare     from the corresponding alkenes using method Example 7, (E).                   j: Methyl 4(2-benzyloxy-5-methylphenethyl)-2-hydroxybenzoate was prepared     as described in Footnote (a) replacing 2benzyloxy-5-bromobenzaldehyde wit     2benzyloxy-5-methylbenzaldehyde.                                              k: Ethyl 6 2-benzyloxyphenethyl!-3-pyridazinecarboxylate was prepared as      follows:                                                                      (A) 1benzyloxy-2-iodobenzene (21.56 g), trimethylsilylacetylene (10.58 ml     (PPh.sub.3).sub.2 Pd Cl.sub.2 (972 mg) and CuI (133 mg) in ethylamine (15     ml) were stirred overnight. The solvent was evaporated, the residue           extracted with diethyl ether, washed with 2N aqueous HCl and brine, then      dried (MgSO.sub.4), filtered and evaporated. The resulting residue was        purified by MPLC on silica gel eluting with CH.sub.2 Cl.sub.2 :hexane         (1:2) to give a brown solid (19.85 g).                                        (B) The brown solid (13.61 g) was dissolved in methanol (150 ml) and 2N       aqueous NaOH (15 ml) was added. After 1 hour the solvent was evaporated       and the residue extracted into diethyl ether, washed with brine, dried        (MgSO.sub.4), filtered and evaporated to give a product (9.93 g).             (C) A mixture of the product from the above step (9.93 g), ethyl              6chloro-3-pyridazinecarboxylate  ref: Aust. J. Chem. 1977, 30, 2319! (4.4     g), (PPh.sub.3).sub.2 Pd Cl.sub.2 (335 mg) and CuI (45 mg) in                 triethylamine (100 ml) was stirred at 50° C. for 4 hours. The          solvent was evaporated and the residue purified by MPLC silica gel elutin     with CH.sub.2 Cl.sub.2 :ethyl acetate mixtures (0:1 to 1:1) followed by       crystallisation from diethyl ether to give ethyl                              6(2-(2-benzyloxyphenyl)ethenyl)-3-pyridazinecarboxylate (2.46 g). The         acetylene was converted to ethyl                                              6 2-benzyloxyphenethyl!-3-pyridazinecarboxylate by method Example 9, (D).     1: Methyl 5 3-(2-benzyloxyphenyl)propyl!-2-pyridinecarboxylate was            prepared using a similar sequence of methods to those described in Exampl     8, using 2benzyloxyphenylacetaldehyde and methyl                              5hydroxymethyl-2-pyridinecarboxylate. The required phosphonium salt was       prepared from methyl 5methanesulphonyloxymethyl-2-pyridine-carboxylate        which was made using standard procedures.                                     m: Methyl 2 2-(2-benzyloxyphenyl) ethenyl!-5pyridinecarboxylate was           prepared from methyl 2methyl-5-pyridinecarboxylate using a similar method     to that described in Example 8 to prepare methyl                              4 2-(2-benzyloxyphenyl)ethenyl!-3-fluorobenzoate.                             n: Methyl 2 2-benzyloxyphenethyl!-5-pyridinecarboxylate was prepared from     methyl 2 2-(2-benzyloxyphenyl)ethenyl!-5-pyridinecarboxylate using a          similar method to that of Example 1, (E) followed by benzylation of the       phenol using a similar method to that of Example 1, (I).                      o: Methyl 2 3-(2-benzyloxyphenyl)propyl!-5-pyridinecarboxylate was            prepared using similar methods to those described in Example 8, using         2benzyloxyphenylacetaldehyde and methyl 2methyl-5-pyridinecarboxylate as      starting materials.                                                           p: Methyl 5 2-(2-benzyloxyphenyl)ethenyl!-2-pyridinecarboxylate was           prepared from 2benzyloxybenzyltriphenylphosphonium bromide and methyl         5formyl-2-pyridinecarboxylate using similar methods to those described in     Example 8.                                                                    q: Methyl 4 3-(2-benzyloxyphenyl)propyl!phenylacetate was prepared by         similar methods to those described in Example 1, (G) and (H) from             2benzyloxyphenylacetaldehyde and 4carboxymethylbenzyltriphenylphosphonium     bromide.                                                                      r: Ethyl 5 3-(2-benzyloxyphenyl)propyl!-2-thiophenecarboxylate was            obtained as follows: Ethyl 2thiophenecarboxylate (25 g) was added to LDA      (1 equivalent) in THF (150 ml) at -78° C. and stirred for 30           minutes. DMF (11.7 g) in THF (50 ml) was added and stirred at -78°     C. for 30 minutes, then warmed to ambient temperature. The solvent was        evaporated and the residue mixed with 2benzyloxy-acetophenone (36.1 g)        (prepared as described in Example 1, (B)) and potassium tertbutoxide (1 g     in ethanol (200 ml) and stirred at 20° C. for 16 hours. The solven     was evaporated, the residue dissolved in methylene chloride (100 ml) and      filtered through silica, the solvent evaporated and the residue triturate     to give ethyl 5 2-(2-benzyloxybenzoyl)-ethenyl)-2-thiophenecarboxylate (4     g). Ethyl 5 2-(2-benzyloxy-benzoyl)ethenyl!-2-thiophenecarboxylate was        converted to ethyl 5 2-(2-benzyloxybenzoyl)ethyl!-2-thiophenecarboxylate      using a similar method to that of Example 1, (E) which was converted to       ethyl 5 3-(2-benzyloxyphenyl)propyl!-2-thiophenecarboxylate using a           similar method to that of Example 1, (F).                                     s: A mixture of methyl 5methylpyrazinecarboxylate (1 g),                      2benzyloxybenzaldehyde (1.53 g), acetic acid (430 mg) and acetic anhydrid     (730 mg) was heated at 140° C. for 22 hours, cooled and purified b     chromatography on silica gel, using CH.sub.2 Cl.sub.2 ethyl acetate (99:1     as eluant. There was thus obtained methyl                                     2 2-(2-benzyloxyphenyl)ethenyl!-5-pyrazinecarboxylate (1.1 g) mpt.            105° C.                                                                t: Methyl 2 2-(2-benzyloxy-5-bromophenyl)ethenyl!-5-pyrazine-carboxylate      was prepared from 2benzyloxy-5-bromobenzaldehyde and methyl                   2methyl-5-pyridine carboxylate using a similar method to that of Example      28, Footnote s.                                                               u: Methyl 2 2-benzyloxy-5-bromophenethyl)-5-pyridinecarboxylate was           prepared from methyl                                                          2 2-(2-benzyloxy-5-bromophenyl)-ethenyl!-5-pyrazinecarboxylate using a        similar method to that of Example 1, (E), separating the product from sid     products by MPLC, eluting with CH.sub.2 Cl.sub.2 :EtOAc (98:2).               v: The ester methyl 2 2-benzyloxyphenethyl!-5-pyridinecarboxylate was         prepared from methyl 2 2-(2-benzyloxyphenyl)ethenyl!-5-pyridinecarboxylat     using a similar method to that of Example 7, (E).                             w: The ester methyl                                                           2 2-(2-benzyloxy-5-methanethiophenyl)-ethenyl!-5-pyrazinecarboxylate was      prepared from 2benzyloxy-5-methanethiobenzaldehyde and methyl                 2methyl-5-pyridinecarboxylate using a similar method to that of Example       28, Footnote k.                                                               x: The ester methyl                                                           2 2-(2-benzyloxy-5-methanesulphonylphenyl)ethenyl!-5-pyrazinecarboxylate      was prepared from methyl                                                      2 2-(2-benzyloxy-5-methanethiophenyl)ethenyl!-5-pyrazinecarboxylate using     a similar method to that of Example 49.                                       y: The esters methyl 4 3-(2-benzyloxy-6-hydroxyphenyl)-propyl!benzoate an     methyl 4 3-(2-benzyloxy-6-benzyloxy-phenyl)propyl!benzoate were prepared      as follows:                                                                   (A) Methyl 4 3-(2,6-dimethoxy)propyl!benzoate was prepared from               2,6dimethoxybenzaldehyde and 4carboxyphenethyltriphenylphosphonium bromid     by similar methods to that of Example 1 (G) and (H).                          (B) Boron tribromide was added to a stirred solution of methyl                4 3-(2,6-dimethoxy)propyl!benzoate (11.31 g) at -78° C. in CH.sub.     Cl.sub.2, then stirred at ambient temperature for 15 hours. The mixture       was cooled (-30° C.) and water added dropwise. The reaction was        poured into EtOAc and the organic layer washed with water, dried              (MgSO.sub.4), filtered and evaporated to give methyl                          4 3-(2,6-dihydroxy)propyl!benzoate as a brown oil (14.65 g).                  (C) A mixture of methyl 4 3-(2,6-dihyroxy)propyl!benzoate (8.13 g), benzy     bromide (3.38 ml) and potassium carbonate (3.86 g) was stirred in DMF for     18 hours. The DMF was evaporated and the residue purified by MPLC on          silica gel eluting with CH.sub.2 Cl.sub.2. Methyl                             4 3-(2-benzyloxy-6-benzyloxyphenyl) propyl!benzoate (4.03 g), methyl          4 3-(2-benzyloxy-6-hydroxyphenyl) propyl!benzoate (2.28 g) and methyl         4 3-(2,6-dihydroxy)propyl!benzoate (2.77 g) were obtained.                    z: Methyl 4 3-(2-benzyloxy-6-methoxyphenyl)propyl!benzoate was prepared a     follows: methyl 4 3-(2,6-dihydroxy, propyl!benzoate (2.92 g), prepared        from the methyl ester by a similar method to that of Example 1 (A), and       conc. H.sub.2 SO.sub.4 (1 drop) in methanol (100 ml) were heated at reflu     for 18 hours. The solvent was evaporated, the residue extracted with          EtOAc, washed with water, dried, filtered and evaporated. The resulting       gum was purified by MPLC on silica gel eluting with CH.sub.2 Cl.sub.2 to      give methyl 4 3-(2-hydroxy-6-methoxyphenyl)propyl!benzoate (2.27 g).          Methyl 4 3-(2-hydroxy-6-methoxyphenyl)propyl!benzoate was converted to        methyl 4 3-(2-benzyloxy-6-methoxyphenyl)propyl!benzoate by a similar          method to that of Example 1, (B).                                             aa: Methyl 2 2-benzyloxy-5-methanethiophenethyl!-5-pyridine-carboxylate       was prepared from the corresponding alkene (Example 28, compound 23) usin     a similar method to that of Example 7, (E).                                   ab: Methyl                                                                    2 2-benzyloxy-5-methanesulphonylphenethyl!-5-pyridinecarboxylate was          prepared from the corresponding sulphide (see footnote (aa) using a           similar method to that of Example 49. Methyl                                  2 2-benzyloxy-5-(methanesulphonylphenethyl!-5-(methoxycarbonyl)-pyridine-    -oxide was obtained as a side product from this reaction.                      ac: Methyl 4 2-2-benzyloxyphenyl)ethenyl!-3-hydroxybenzoate was prepared      from methyl 2acetoxy-4-methylbenzoate and 2benzyloxybenzaldehyde using        similar processes to those described in Example 8 and purified by             crystallisation from ethyl acetate/hexane mixtures.                           ad: Methyl 4 2-(2-benzyloxyphenyl)ethenyl!-3-methoxybenzoate was prepared     from methyl 4 2-(2-benzyloxyphenyl)ethenyl!-3-hydroxybenzoate by a simila     method to that of Example 1 (I).                                              ae: Methyl 4 2-benzyloxyphenethyl!-3-hydroxybenzoate was prepared from        methyl 4 2-(2-benzyloxyphenyl)ethenyl!-3-hydroxybenzoate by a similar         method to that of Example 7, (E).                                             af: Methyl 4 2-benzyloxyphenethyl!-3-methoxybenzoate was made from methyl     4 2-(2-benzyloxyphenyl)ethenyl!-3-methoxybenzoate by a similar method to      that of Example 1, (E) using ethanol/THF as the solvent and stopping the      reaction after the absorption of 1.1 equivalents of hydrogen gas.             ag: Methyl 4 2-(2-benzyloxyphenyl)-(Z)-ethenyl!-3-bromobenzoate was           prepared from methyl 3bromo-4-methylbenzoate and 2benzyloxybenzaldehyde       using similar processes to those described in Example 8. It was purified      by MPLC on silica gel eluting with CH.sub.2 Cl.sub.2 :hexane (3:7)            followed by crystallisation from diethyl ether/hexane mixtures (mpt           78.5-79.5° C).                                                         ah: Methyl 4 2-benzyloxyphenethyl!-3-bromobenzoate was prepared from a        mixture of the alkenes methyl                                                 4 2-(2-benzyloxyphenyl)ethenyl!-3-bromobenzoate using a similar method to     that of Example 7, (E).                                                       ai: Methyl 4 2-benzyloxyphenethyl!-3-cyanobenzoate was prepared from          methyl 4 2-benzyloxyphenethyl)-3-bromobenzoate by a similar method to tha     of Example 3, Footnote n.                                                     aj: Methyl 4 2-benzyloxyphenethyl!-3-phenylsulphonylaminobenzoate was         prepared from methyl 4 2-benzyloxyphenethyl)-3-aminobenzoate using a          similar method to that of Example 3, Footnote g, using triethylamine in       place of potassium carbonate.                                                 ak: Methyl 4 2-benzyloxyphenethyl!-3-(2,2-dimethylpropionylaminobenzoate      was prepared from methyl 4 2-benzyloxyphenethyl)-3-aminobenzoate by a         similar method to that of example 2 footnote b. using tBuCOCl in place of     acetic anhydride.                                                             al: Methyl 4 3-(2-benzyloxyphenyl)propyl!-2-bromobenzoate was prepared        from 2benzyloxyphenylacetaldehyde and methyl 3bromo-4-methylbenzoate usin     a similar process to that described in example 8. The final step to reduc     the mixture of alkenes was carried out using a similar method to that of      example 7 (E).                                                                am: Methyl 4 3-(2-benzyloxyphenyl)propyl!-2-cyanobenzoate was prepared        from methyl 4 3-(2-benzyloxyphenyl)propyl!-2-bromobenzoate by a similar       method to that of example 3 footnote n.                                       an: Methyl 4 2-(2-benzyloxyphenyl)ethenyl!-3,5-dibromobenzoate was            prepared from 2benzyloxybenzaldehyde and methyl                               3,5dibromo-4-methylbenzoate using a similar processe to that described in     example 8.                                                                    ao: Ethyl 4 2-benzyloxyphenethyl)-3,5-dibromobenzoate was prepared from       methyl 4 2-(2-benzyloxyphenyl)ethenyl!-3,5-dibromobenzoate by a similar       method to that of example 7(E), modifying the conditions by carrying out      the reaction for 60 hours. During this time ester exchange occured giving     the ethyl ester.                                                              ap: Methyl 4 3-(2-benzyloxyphenyl)propyl!-3-methoxybenzoate was prepared      from methyl 3methoxy-4-methylbenzoate and 2benzyloxyphenylacetaldehyde        using a similar process to that described in Example 8. The final             reduction step was carried out using a modification of the method of          Example 1, (E) in which 5% Pd/BaSO.sub.4 was added as the hydrogenation       catalyst.                                                                     aq: A mixture of (Z) and (E) alkenes of methyl                                4 2-(2-benzyloxy-5-chlorophenyl)ethenyl!-3-methoxybenzoate was prepared       using similar processes to those described in Example 8, starting with        2benzyloxy-5-chlorobenzaldehyde and methyl 3methoxy-4-bromomethylbenzoate     The isomeric esters were separated and isolated by fractional                 crystallisation from ethyl acetate/hexane mixtures.                           ar: The ester methyl 4 2-benzyloxy-5-chlorophenethyl!-3-methoxybenzoate       was prepared from a mixture of the (Z) and (E) alkenes by a similar metho     to that of Example 7, (E).                                                    as: Methyl 4 2-benzyloxyphenethyl!-3-acetylaminobenzoate was synthesised      from methyl 4 2-benzyloxyphenethyl!-3-aminobenzoate by a similar method t     that of Example 2, Footnote b, using CH.sub.3 COCl in place of Ac.sub.2 O                                                                              

Footnotes

a:- Methyl 4-(2-(benzyloxy-5-bromophenethyl)-2-hydroxybenzoate wasprepared from a Z/E mixture of methyl 4-2-(2-benzyloxy-5-bromopenyl)ethenyl!-2-hydroxybenzoate using a similarmethod to that of ample 7 (E). The alkenes were prepared from2-benzyloxy-5-bromobenzaldehyde and4-methoxycarbonyl-3-acetoxybenzyl-triphenylphosphonuim bromide by asimilar method to that of Example 8 (E) in the course of which theacetate group was hydrolysed.

b:- Methyl 4-(2-benzyloxy-5-bromophenethyl)-2-methoxybenzoate wasprepared from methyl 4-(2-benzyloxy-5-bromophenethyl)-2-hydroxybenzoateusing a similar method to that of Example 2, Footnote C (A) replacingallyl bromide with methyl iodide.

c:- Methyl4-{2-(2-benzyloxy-5-methanethiophenyl)ethenyl!-2-methoxybenzoate wasprepared from methyl 4-2-(2-benzyloxy-5-methanethiophenyl)ethenyl!-2-hydroxybenzoate using asimilar method to that of Example 2, Footnote C (A) replacing allylbromide with methyl iodide.

Methyl 4- 2-(2-benzyloxy-5-methanethiophenyl)ethenyl!-2-hydroxybenzoatewas prepared from 2-benzyloxy-4-methanethiobenzaldehyde and4-methoxycarbonyl-3-acetoxybenzyltriphenylphosphonium bromide using asimilar method to that of Example 8, (E) in the course of which theacetate group was hydrolysed. The required E isomer was obtained fromthe mixture of Z and E isomers by separation using MPLC on silica gel.

d:- See second part of note (c).

e:- Methyl 4- 2-benzyloxy-5-methanethiophenethyl)-2-hydroxybenzoate wasprepared from the corresponding alkenes using a similar method of thatof Example 7, (E).

f:- Methyl 4- 2-benzyloxy-5-methanethiophenethyl)-2-methoxybenzoate wasprepared from methyl 4-2-benzyloxy-5-methanethiophenethyl)-2-hydroxybenzoate using a similarmethod to that a Example 2, Footnote c, (A) replacing allyl bromide withmethyl iodide.

f:- Methyl 4- 2-benzyloxy-5-methanesulphonylphenethyl)-2-hydroxybenzoatewas prepared from the corresponding sulphide using a modification of themethod of Example 49, in which the reaction was carried out at 0° C.

h:- Methyl 4- 2-(2-benzyloxy-5-methoxyphenyl)ethenyl!-2-hydroxybenzoatewas prepared by the second part of the method described in Footnote (c)using 2-benzyloxy-5-methoxybenzaldehyde in place of2-benzyloxy-5-methylthiobenzaldehyde.

i:- Methyl 4-(2-benzyloxy-5-methoxyphenethyl)-2-hydroxybenzoate wasprepared from the corresponding alkenes using method Example 7, (E).

j:- Methyl 4-(2-benzyloxy-5-methylphenethyl)-2-hydroxybenzoate wasprepared as described in Footnote (a) replacing2-benzyloxy-5-bromobenzaldehyde with 2-benzyloxy-5-methylbenzaldehyde.

k:- Ethyl 6- 2-benzyloxyphenethyl!-3-pyridizinecarboxylate was preparedas follows:

(A) 1-benzyloxy-2-iodobenzene (21.56 g), trimethylsilylacetylene (10.58ml) (PPh₃)₂ Pd Cl₂ (972 mg) and CuI (133 mg) in ethylamine (150 ml) werestirred overnight. The solvent was evaporated, the residue extractedwith diethyl ether, washed with 2N aqueous HCl and brine, then dried(MgSO₄), filtered and evaporated. The resulting residue was purified byMPLC on silica gel eluting with CH₂ Cl₂ :hexane (1:2) to give a brownsolid (19.85 g).

(B) The brown solid (13.61 g) was dissolved in methanol (150 ml) and 2Naqueous NaOH (15 ml) was added. After 1 hour the solvent was evaporatedand the residue extracted into diethyl ether, washed with brine, dried(MgSO₄), filtered and evaporated to give a product (9.93 g).

(C) A mixture of the product from the above step (9.93 g), ethyl6-chloro-3-pyridazinecarboxylate ref: Aust. J. Chem. 1977, 30, 2319!(4.45 g), (PPh₃)₂ Pd Cl₂ (335 mg) and CuI (45 mg) in triethylamine (100ml) was stirred at 50° C. for 4 hours. The solvent was evaporated andthe residue purified by MPLC on silica gel eluting with CH₂ Cl₂ : ethylacetate mixtures (0:1 to 1:1) followed by crystallisation from diethylether to give ethyl 6-2-(2-benzyloxyphenyl)ethenyl)-3-pyridazinecarboxylate (2.46 g). Theacetylene was converted to ethyl 6-2-benzyloxyphenethyl!-3-pyridazinecarboxylate by method Example 9, (D).

l:- Methyl 5-(3-(2-benzyloxyphenyl)propyl!-2-pyridinecarboxylate wasprepared using a similar sequence of methods to those described inExample 8, using 2-benzyloxyphenylacetaldehyde and methyl5-hydroxymethyl-2- pyridinecarboxylate. The required phosphonium saltwas prepared from methyl5-methanesulphonyloxymethyl-2-pyridine-carboxylate which was made usingstandard procedures.

m:- Methyl 2- 2-(2-benzyloxyphenyl)ethenyl!-5-pyridinecarboxylate wasprepared from methyl 2-methyl-5-pyridinecarboxylate using a similarmethod to that described in Example 8 to prepare methyl 4-2-(2-benzyloxyphenyl)ethenyl)-3-fluorobenzoate.

n:- Methyl 2- 2-benzyloxyphenethyl!-5-pyridinecarboxylate was preparedfrom methyl 2- 2-(2-benzyloxyphenyl)ethenyl!-5-pyridinecarboxylate usinga similar method to that of Example 1, (E) followed by benzylation ofthe phenol using a similar method to that of Example 1, (I).

o:- Methyl 2- 3-(2-benzyloxyphenyl)propyl)-5-pyridinecarboxylate wasprepared using similar methods to those described in Example 8, using2-benzyloxyphenylacetaldehyde and methyl 2-methyl-5-pyridinecarboxylateas starting materials.

p:- Methyl 5- 2-(2-benzyloxyphenyl)ethenyl!-2-pyridinecarboxylate wasprepared from 2-benzyloxybenzyltriphenylphosphonium bromide and methyl5-formyl-2-pyridinecarboxylate using similar methods to those describedin Example 8.

q:- Methyl 4- 3-(2-benzyloxyphenyl)propyl!phenylacetate was prepared bysimilar methods to those described in Example 1, (G) and (H) from2-benzyloxyphenylacetaldehyde and4-carboxymethylbenzyltriphenylphosphonium bromide.

r:- Ethyl 5- 3-(2-benzyloxyphenyl) propyl!-2-thiophenecarboxylate wasobtained as follows:- Ethyl 2-thiophenecarboxylate (25 g) was added toLDA (1 equivalent) in THF (150 ml) at -78° C. and stirred for 30minutes. DMF (11.7 g) in THF (50 ml) was added and stirred at -78° C.for 30 minutes, then warmed to ambient temperature. The solvent wasevaporated and the residue mixed with 2-benzyloxy-acetophenone (36.1 g)(prepared as described in Example 1, (B)) and potassium tert-butoxide (1g) in ethanol (200 ml) and stirred at 20° C. for 16 hours. The solventwas evaporated, the residue dissolved in methylene chloride (100 ml) andfiltered through silica, the solvent evaporated and the residuetriturated to give ethyl 5-2-(2-benzyloxybenzoyl)-ethenyl!-2-thiophenecarboxylate (47 g). Ethyl 5-2-(2-benzyloxybenzoyl)ethenyl!-2-thiophenecarboxylate was converted toethyl 5- 2-(2-benzyloxybenzoyl)ethenyl!-2-thiophenecarboxylate using asimilar method to that of Example 1, (E) which was converted to ethyl 5-3-(2-benzyloxyphenyl)propyl!-2-thiophenecarboxylate using a similarmethod to that of Example 1, (F).

s:- A mixture of methyl 5-methylpyrazinecarboxylate (1 g),2-benzyloxybenzaldehyde (1.53 g), acetic acid (430 mg) and aceticanhydride (730 mg) was heated at 140° C. for 22 hours, cooled andpurified by chromatography on silica gel, using CH₂ Cl₂ ethyl acetate(99:1) as eluant. There was thus obtained methyl 2-2-(2-benzyloxyphenyl)ethenyl!-5-pyrazinecarboxylate (1.1 g) mpt. 105° C.

t:- Methyl 2-2-(2-benzyloxy-5-bromophenyl)ethenyl!-5-pyrazine-carboxylate wasprepared from 2-benzyloxy-5-bromobenzaldehyde and methyl2-methyl-5-pyridine carboxylate using a similar method to that ofExample 28, Footnote s.

u:- Methyl 2- 2-benzyloxy-5-bromophenethyl!-5-pyridinecarboxylate wasprepared from methyl 2-2-(2-benzyloxy-5-bromophenyl)-ethenyl!-5-pyrazinecarboxylate using asimilar method to that of Example 1, (E), separating the product fromside products by MPLC, eluting with CH₂ Cl₂ : EtOAc (98:2).

v:- The ester methyl 2- 2-benzyloxyphenethyl!-5-pyridinecarboxylate wasprepared from methyl 2-2-(2-benzyloxyphenyl)ethenyl!-5-pyridinecarboxylate using a similarmethod to that of Example 7, (E).

w:- The ester methyl 2-2-(2-benzyloxy-5-methanethiophenyl)-ethenyl!-5-pyrazinecarboxylate wasprepared from 2-benzyloxy-5-methanethiobenzaldehyde and methyl2-methyl-5-pyridinecarboxylate using a similar method to that of Example28, Footnote k.

x:- The ester methyl 2-(2-(2-benzyloxy-5-methanesulphonylphenyl)ethenyl!-5-pyrazinecarboxylate was prepared from methyl 2-2-(2-benzyloxy-5-methanethiophenyl)ethenyl!-5-pyrazinecarboxylate usinga similar method to that of Example 49.

y:- The esters methyl 4-(3-(2-benzyloxy-6-hydroxyphenyl)-propyl!benzoateand methyl 4- 3-(2-benzyloxy-6-benzyloxyphenyl)propyl!benzoate wereprepared as follows:

(A) Methyl 4-(3-(2,6-dimethoxy)propyl!benzoate was prepared from2,6-dimethoxybenzaldehyde and 4-carboxyphenethyltriphenylphosphoniumbromide by similar methods to that of Example 1 (G) and (H).

(B) Boron tribromide was added to a stirred solution of methyl4-(3-(2,6-dimethoxy)propyl!benzoate (11.31 g) at -78° C. in CH₂ Cl₂,then stirred at ambient temperature for 15 hours. The mixture was cooled(-30° C.) and water added dropwise. The reaction was poured into EtOAcand the organic layer washed with water, dried (MgSO₄), filtered andevaporated to give methyl 4-(3-(2,6-dihydroxy)propyl!benzoate as a brownoil (14.65 g).

(C) A mixture of methyl 4- 3-(2,6-dihydroxy)propyl!benzoate (8.13 g),benzyl bromide (3.38 ml) and potassium carbonate (3.86 g) was stirred inDMF for 18 hours. The DMF was evaporated and the residue purified byMPLC on silica gel eluting with CH₂ Cl₂. Methyl 4-3-(2-benzyloxy-6-benzyloxyphenyl) propyl!benzoate (4.03 g), methyl4-(3-(2-benzyloxy-6-hydroxyphenyl) propyl!benzoate (2.28 g) and methyl4-(3-(2,6-dihydroxy)propyl!benzoate (2.77 g) were obtained.

z:- Methyl 4-(3-(2-benzyloxy-6-methoxyphenyl)propyl)benzoate wasprepared as follows: methyl 4- 3-(2,6-dihydroxy)propyl!benzoate (2.92g), prepared from the methyl ester by a similar method to that ofExample 1 (A), and conc. H₂ SO₄ (1 drop) in methanol (100 ml) wereheated at reflux for 18 hours. The solvent was evaporated, the residueextracted with EtOAc, washed with water, dried, filtered and evaporated.The resulting gum was purified by MPLC on silica gel, eluting with CH₂Cl₂ to give methyl 4- 3-(2-hydroxy-6-methoxyphenyl) propyl!benzoate(2.27 g).

Methyl 4- 3-(2-hydroxy-6-methoxyphenyl)propyl!benzoate was converted tomethyl 4- 3-(2-benzyloxy-6-methoxyphenyl)propyl!benzoate by a similarmethod to that of Example 1, (B).

aa:- Methyl 2-2-benzyloxy-5-methanethiophenethyl!-5-pyridine-carboxylate was preparedfrom the corresponding alkene (Example 28, compound 23) using a similarmethod to that of Example 7, (E).

ab:- Methyl 2-2-benzyloxy-5-methanesulphonylphenethyl!-5-pyridinecarboxylate wasprepared from the corresponding sulphide (see footnote (aa) using asimilar method to that of Example 49. Methyl 2- 2-benzyloxy-5-methanesulphonylphenethyl!-5-(methoxycarbonyl)-pyridine-1-oxide wasobtained as a side product from this reaction.

ac:- Methyl 4- 2-(2-benzyloxyphenyl)ethenyl!-3-hydroxybenzoate wasprepared from methyl 2-acetoxy-4-methylbenzoate and2-benzyloxybenzaldehyde using similar processes to those described inExample 8 and purified by crystallisation from ethyl acetate/hexanemixtures.

ad:- Methyl 4- 2-(2-benzyloxyphenyl)ethenyl)-3-methoxybenzoate wasprepared from methyl4- 2-(2-benzyloxyphenyl) ethenyl!-3-hydroxybenzoateby a similar method to that of Example 1 (I).

ae:- Methyl 4-(2-benzyloxlphenethyl!-3-hydroxybenzoate was prepared frommethyl 4- 2-(2-benzyloxyphenyl)ethenyl)-3-hydroxybenzoate by a similarmethod to that of Example 7, (E).

af:- Methyl 4-(2-benzyloxlphenethyl!-3-methoxybenzoate was made frommethyl 4- 2-(2-benzyloxyphenyl)ethenyl!-3-methoxybenzoate by a similarmethod to that of Example 1, (E) using ethanol/THF as the solvent andstopping the reaction after the absorption of 1.1 equivalents ofhydrogen gas.

ag:- Methyl 4- 2-(2-benzyloxyphenyl)-(Z)-ethenyl!-3-bromobenzoate wasprepared from methyl 3-bromo-4-methylbenzoate and2-benzyloxybenzaldehyde using similar processes to those described inExample 8. It was purified by MPLC on silica gel eluting with CH₂ Cl₂ :hexane (3:7)-followed by crystallisation from diethyl ether/hexanemixtures (mpt 73.5°-79.5° C.).

ah:- Methyl 4- 2-benzyloxyphenethyl!-3-bromobenzoate was prepared from amixture of the alkenes methyl 4-2-(2-benzyloxyphenyl)ethenyl!-3-bromobenzoate using a similar method tothat of Example 7, (E).

ai:- Methyl 4- 2-benzyloxyphenethyl!-3-cyanobenzoate was prepared frommethyl 4- 2-benzyloxyphenethyl!-3-bromobenzoate by a similar method tothat of Example 3, Footnote n.

aj:- Methyl 4- 2-benzyloxyphenethyl!-3-phenylsulphonylaminobenzoate wasprepared from methyl 4- 2-benzyloxyphenethyl!-3-aminobenzoate using asimilar method to that of Example 3, Footnote g, using triethylamine inplace of potassium carbonate.

ak:- Methyl 4-2-benzyloxyphenethyl!-3-(2,2-dimethylpropionylaminobenzoate was preparedfrom methyl 4- 2-benzyloxyphenethyl!-3-aminobenzoate by a similar methodto that of example 2 footnote b. using tBuCOCl in place of aceticanhydride.

al:- Methyl 4- 3-(2-benzyloxyphenyl)propyl!-2-bromobenzoate was preparedfrom 2-benzyloxyphenylacetaldehyde and methyl 3-bromo-4-methylbenzoateusing a similar process to that described in example 8. The final stepto reduce the mixture of alkenes was carried out using a similar methodto that of example 7(E).

am:- Methyl 4- 3-(2-benzyloxyphenyl)propyl)-2-cyanobenzoate was preparedfrom methyl 4-(3-(2-benzyloxyphenyl)propyl)-2-bromobenzoate by a similarmethod to that of example 3 footnote n.

an:- Methyl 4- 2-(2-benzyloxyphenyl)ethenyl!-3,5-dibromobenzoate wasprepared from 2-benzyloxybenzaldehyde and methyl3,5-dibromo-4-methylbenzoate using a similar process to that describedin example 8.

ao:- Ethyl 4- 2-benzyloxyphenethyl!-3,5-dibromobenzoate was preparedfrom methyl 4- 2-(2-benzyloxyphenyl)ethenyl!-3,5-dibromobenzoate by asimilar method to that of example 7(E), modifying the conditions bycarrying out the reaction for 60 hours. During this time ester exchangeoccurred giving the ethyl ester.

ap:- Methyl 4- 3-(2-benzyloxyphenyl)propyl!-3-methoxybenzoate wasprepared from methyl 3-methoxy-4-methylbenzoate and2-benzyloxyphenylacetaldehyde using a similar process to that describedin Example 8. The final reduction step was carried out using amodification of the method of Example 1, (E) in which 5% Pd/BaSO₄ wasadded as the hydrogenation catalyst.

aq:- A mixture of (Z) and (E) alkenes of methyl 4-2-(2-benzyloxy-5-chlorophenyl)ethenyl!-3-methoxybenzoate was preparedusing similar processes to those described in Example 8, starting with2-benzyloxy-5-chlorobenzaldehyde and methyl3-methoxy-4-bromomethylbenzoate. The isomeric esters were separated andisolated by fractional crystallisation from ethyl acetate/hexanemixtures.

ar:- The ester methyl4-(2-benzyloxy-5-chlorophenethyl!-3-methoxybenzoate was prepared from amixture of the (Z) and (E) alkenes by a similar method to that ofExample 7, (E).

as:- Methyl 4- 2-benzyloxyphenethyl!-3-acetylaminobenzoate wassynthesised from methyl 4- 2-benzyloxyphenethyl!-3-aminobenzoate by asimilar method to that of Example 2, Footnote b, using CH₃ COCl in placeof Ac₂ O.

EXAMPLE 29

The process of Example 84 (A) was repeated with the appropriate nitrilesto give the compounds described in the following table:

    __________________________________________________________________________     ##STR62##                                                                    Compound                                                                            R  X    Ar            mpt   Footnote                                    __________________________________________________________________________    1     H                                                                       (CH.sub.2).sub.2 -                                                                   ##STR63##                                                                       259.5-260.5                                                                        a                                                               2     H                                                                       (CH.sub.2).sub.3 -                                                                  "  181-182                                                                            a                                                               3     H                                                                       (CH.sub.2).sub.2 -                                                                   ##STR64##                                                                       176-178                                                                            a                                                               4     H                                                                       (CH.sub.2).sub.3 -                                                                  "  181.5-183                                                                          a                                                               5     5-Cl                                                                    (CH.sub.2).sub.2 -                                                                  "  184.5-186                                                                          a                                                               6     5-Cl                                                                    (CH.sub.2).sub.2 -                                                                   ##STR65##                                                                       244-245                                                                            b                                                               7     5-Br                                                                    (CH.sub.2).sub.2 -                                                                   ##STR66##                                                                       191-193                                                              8     5-Br                                                                    (CH.sub.2).sub.2 -                                                                   ##STR67##                                                                       196-198                                                              9     5-Br                                                                    (CH.sub.2).sub.2 -                                                                   ##STR68##                                                                       250-255                                                                            c                                                               __________________________________________________________________________     Footnotes                                                                     a: The relevant nitrile precursors were prepared from the corresponding       primary amides as exemplified by the following method: Trifluoroacetic        anhydride (0.75 ml) was added to a mixture of                                 4 2-benzyloxyphenethyl!-3-bromobenzamide (1.46 g) and pyridine (0.86 ml)      in THF at -20° C. The mixture was stirred at ambient temperature       for 18 hours, diluted with ethyl acetate and washed with water, dried         (MgSO.sub.4), filtered and evaporated to dryness. The resulting residue       was purified by MPLC on silica gel, eluting with CH.sub.2 Cl.sub.2 to giv     4 2-benzyloxyphenethyl!-3-bromobenzonitrile as a white solid (1.34 g).        b: ptolunitrile (1.17 g) in THF (20 ml) was added to a solution of LDA        (1.1 equivalents) in THF at -70° C. After 5 minutes,                   2benzyloxy-5-chlorobenzyl bromide (2.33 g) in THF (20 ml) was added           dropwise to the reaction mixture at -70° C. The mixture was poured     into 50% aqueous saturated ammonium chloride solution and extracted with      ethyl acetate. The organic layer was washed (brine), dried and evaporated     The residue was subjected to chromatography an 7734 silica gel, (eluting      with CH.sub.2 Cl.sub.2 : hexane mixture (2.5:97.5 to 50:50) to give           4 2-benzyloxy-5-chlorophenethyl!benzonitrile (1.4 g) mpt 77-79° C.     c: The nitrile                                                                Ncyanomethyl-6- 2-benzyloxy-5-bromophenethyl!-2-oxo-1H-pyridine-3-carboxa    ide was prepared from                                                          6 2-benzyloxy-5-bromophenethyl!-2-oxo-1H-pyridine-3-carboxylic acid by        method.                                                                  

Footnotes

a:- The relevant nitrile precursors were prepared from the correspondingprimary amides as exemplified by the following method:

Trifluoroacetic anhydride (0.75 ml) was added to a mixture of 4-2-benzyloxyphenethyl!-3-bromobenzamide (1.46 g) and pyridine (0.86 ml)in THF at -20° C. The mixture was stirred at ambient temperature for 18hours, diluted with ethyl acetate and washed with water, dried (MgSO₄),filtered and evaporated to dryness. The resulting residue was purifiedby MPLC on silica gel, eluting with CH₂ Cl₂ to give 4-2-benzyloxyphenethyl!-3-bromobenzonitrile as a white solid (1.34 g).

b:- p-tolunitrile (1.17 g) in THF (20 ml) was added to a solution of LDA(1.1 equivalents) in THF at -70° C. After 5 minutes,2-benzyloxy-5-chlorobenzyl bromide (2.33 g) in THF (20 ml) was addeddropwise to the reaction mixture at -70° C. The mixture was poured into50% aqueous saturated ammonium chloride solution and extracted withethyl acetate. The organic layer was washed (brine), dried andevaporated. The residue was subjected to chromatography an 7734 silicagel, (eluting with CH₂ Cl₂ : hexane mixture (2.5:97.5 to 50:50) to give4- 2-benzyloxy-5-chlorophenethyl!benzonitrile (1.4 g) mpt 77°-79° C.

c:- The nitrileN-cyanomethyl-6-(2-benzyloxy-5-bromophenethyl)-2-oxo-1H-pyridine-3-carboxamidewas prepared from 6-2-benzyloxy-5-bromophenethyl!-2-oxo-1H-pyridine-3-carboxylic acid bymethod.

EXAMPLE 30

4- 3-(2-Benzyloxy-4-bromophenyl)propyl!benzoic acid

4- 3-(2-Benzyloxy-4-bromophenyl)propyl!benzoic acid (mpt 141°-142° C.)was prepared from a mixture of 4-3-(2-benzyloxy-4-bromophenyl)prop-2-enyl!benzoic acid and 4-3-(2-benzyloxy-4-bromophenyl)prop-1-enyl!benzoic acid by a similarmethod to that of Example 7, (E). The mixture of alkenes was preparedfrom 2-benzyloxy-4-bromobenzaldehyde and4-carboxyphenethyltriphenylphosphonium bromide by a similar method tothat of Example 1, (G).

EXAMPLE 31

4- 3-(2-Benzyloxy-5-chlorophenyl)prop-1-enyl!benzoic acid

4- 3-(2-Benzyloxy-5-chlorophenyl)prop-1-enyl!benzoic acid (mpt 157°-150°C.) was prepared by a similar method to that of Example 1, (G) from2-benzyloxy-5- chlorobenzaldehyde and was purified from a mixture ofisomers by fractional crystallisation from ethyl acetate:hexanemixtures.

EXAMPLE 32 4- 3-(2-Benzyloxy-5-iodophenyl-propyl!benzoic acid

To a solution of 4- 3-(2-benzyloxyphenethyl)propyl!benzoic acid (3.5 g)in acetic acid 100 ml) was added benzyltrimethylammonium dichloroiodate(3.6 g) and anhydrous zinc dichloride (2.0 g). The mixture was stirredfor 18 hours. A pink precipitate formed and was isolated by filtrationand washed with cold acetic acid. The solid was partitioned betweendiethyl ether and 2N HCl solution. The organic layer was separated,dried (MgSO₄) and evaporated. The residue was purified bycrystallisation from dichloromethane:hexane mixtures to give the titlecompound (2.5 g) (mpt. 139°-140 ° C.).

EXAMPLE 33

The following compounds were prepared using a similar procedure to thatdescribed in Example 30 with the modifications described in the notes.

    ______________________________________                                         ##STR69##                                                                    Compound   R           mpt      footnote                                      ______________________________________                                        1          4-Cl        142-143  a                                             2          4-F         143-144  b                                             3          4-CO.sub.2 CH.sub.2 Ph                                                                    --       c                                             4          4,5-(CH.sub.2).sub.4 -                                                                    134-135  b                                             ______________________________________                                         Notes                                                                         a: The mixture of alkenes was converted to the title compound as follows:     A mixture of 4 3-(2-benzyloxy-4-chlorophenyl)prop-2-enyllbenzoic acid and     4 3-(2-benzyloxy-4-chlorophenyl)-prop-1-enyl!benzoic acid (1.6 g) and 5%      PdBaSO.sub.4 (200 mg) in ethyl acetate (70 ml) was stirred under 1            atmosphere of hydrogen for 1.5 hours. The catalyst was removed by             filtration and the mixture evaporated to dryness. The residue was purifie     by flash chromatography on silica gel eluting with diethyl ether:hexane       (1:1) to give compound 1 (0.5 g).                                             b: The mixture of alkenes was converted to the title compound using a         similar method to that of Example 33, Footnote a.                             c: The aldehyde benzyl 4benzyloxy-3-formylbenzoate was made from              4hydroxy-3-formylbenzoic acid (commercially available) by method Example      1, (I) using 2 equivalents of benzyl bromide.                            

EXAMPLE 34 4- 3-(2-Benzyloxy-4-hydroxyphenyl)-propyl!benzoic acid

The title compound was prepared from 4-3-(2-benzyloxy-4-methoxyphenyl)propyl!benzoic acid as follows:

To a solution of 4- 3-(2-benzyloxy-4-methoxyphenyl)-propyl!benzoic acid(0.75 g) in DMSO (20 ml) was added sodium cyanide (0.5 g). The reactionmixture was heated at 190° C. for 40 hours, cooled, partitioned between1N aqueous NaOH and diethyl ether. The aqueous layer was separated,acidified to pH1 (conc. HCl) and extracted with ethyl acetate. Theorganic solution was dried (MgSO₄), filtered and evaporated. The residuewas purified by chromatography on silica gel eluting with diethyl ether,and crystallisation from CH₂ Cl₂ /hexane mixtures to give the titlecompound (150 mg).

EXAMPLE 35 4- 3-(2-Benzyloxy-4-cyanophenyl)propyl!benzoic acid

(A) Benzyl 4- 3-(2-hydroxy-4-cyanophenyl)propyl)benzoate was convertedto the title compound by a similar method to that of Example 1, (A). Theproduct was purified by trituration with diethyl ether. Benzyl 4-3-(2-hydroxy-4- cyanophenyl)propyl)benzoate was prepared as follows:

4- 3-(2-Hydroxy-4-cyanophenyl)propyl)benzoic acid was converted tobenzyl 4- 3-(2-benzyloxy-4-cyanophenyl)propylbenzoate by a similarmethod to that of Example 1, (I) using two equivalents of benzyl bromideand potassium carbonate.

(B) 4- 3-(2-Hydroxy-4-cyanophenyl)propyl)benzoic acid was obtained asfollows:

To a solution of 2-benzyloxy-4-bromobenzaldehyde (11.5 g) in toluene(100 ml) was added ethanediol (3.0 ml) and p-toluene sulphonic acid (100mg). The mixture was heated under reflux for 2 hours, cooled, washedwith aqueous NaHCO₃ solution, dried (MgSO₄), filtered and evaporated togive 2-(2-benzyloxy-4-bromophenyl)-3-dioxolane as an oil (12.5 g).

(C) A mixture of 2-(2-benzyloxy-4-bromophenyl)-3-dioxolane (3.0 g) andCuCN (1.4 g) in NMP (25 ml) was heated at 150° C. The mixture wascooled, poured into diethyl ether and 2N aqueous HCl solution andstirred. The layers were separated and the organic solution dried(MgSO₄), filtered and evaporated. The residue was purified bychromatography on silica gel eluting with diethyl ether to give2-benzyloxy-4-cyanobenzaldehyde (300 mg).

(D) 2-Benzyloxy-4-cyanobenzaldehyde and4-carboxyphenethyltriphenylphosphonium bromide were converted to amixture of 4- 3-(2-benzyloxy-4-cyanophenyl)prop-2-enyl!benzoic acid and4- 3-(2-benzyloxy -4-cyanophenyl)prop-1-enyl!benzoic acid by a similarmethod to that of Example 1, (G). The alkenes were converted to therequired 4- 3-(2-hydroxy-4-cyanophenyl)propyl)benzoic acid by a similarmethod to that of Example 33, Footnote a.

EXAMPLE 36 4- 3-(2-Benzyloxy-5-(N-methylcarbamoyl)phenyl)propyl!benzoicacid

To a 33% solution (16 ml) of methylamine in ethanol was added 4-3-(2-benzyloxy-5-benzyloxycarbonylphenyl)propyl!benzoic acid (1.25 g).The mixture was heated at 100° C. for 12 hours in an autoclave. Thesolvent was evaporated and the residue extracted with ethyl acetate (100ml) and washed with 1N aqueous HCl (100 ml) , dried (MgSO₄), filteredand evaporated. The residue was subjected to chromatography on silicagel, eluting with EtOAc. The title product was purified by triturationwith diethyl ether (150 mg) mpt. 163°-166° C.

EXAMPLE 37 4- 3-(2-benzyloxy-6-methoxynaphthyl),propyl!benzoic acid

To a solution of 4- 3-(2-hydroxy-5,6,7,8-(tetrahydro-1-naphthyl))propyl!benzoic acid (400 mg) in ethanol (50 ml), under argon, was added (DDQ)(500 mg). The solution was stirred for 2 hours, DDQ (200 mg) was addedand the mixture stirred for 18 hours. The solvent was evaporated and theresidue subjected to chromatography on silica gel, eluting with diethylether to give the title compound (200 mg).

EXAMPLE 38 4-3-(3-Benzyloxy-8-oxo-5,6,7,8-tetrahydro-2-naphthyl)propyl!benzoic acid

To a solution of 4- 3-(3-benzyloxy-5,6,7,8-tetrahydro-2-naphthyl)propyl!benzoic acid (1.6 g) in ethyl acetate (50 ml) was added water (1ml) and 2,3-dichloro-5,6-dicyanobenzoquinone (1.9 g). The mixture wasstirred for 2 hours, the solvent evaporated and the residue subjected tochromatography on silica gel, eluting with 0.1% formic acid in EtOAc.The residue was purified by trituration with diethyl ether to give thetitle compound (0.3 g) mpt. 155°-160° C.

EXAMPLE 39 4-3-(3-Benzyloxy-8-hydroxyimino-5,6,7,8-tetrahydro-2-naphthyl)propyl!benzoic acid

4- 3-(3-Benzyloxy-8-oxo-5,6,7,8-tetrahydro-2-naphthyl)propyl! benzoicacid was converted to the title compound by a similar method to that ofExample 3, Footnote q.

EXAMPLE 40 4- 3-(2-Benzyloxy-4-acetylaminophenyl)propyl!benzoic acid

Ethyl 4- 3-(2-benzyloxy-4-acetylaminophenyl)propyl!benzoate wasconverted to the title compound by a similar method to that of Example1, (A) (mpt. 179°-180° C.

Ethyl 4- 3-(2-benzyloxy-4-acetylaminophenyl)propyl!benzoate was preparedas follows:

A mixture of N-(3-allyloxyphenyl)acetamide (13.2 g) prepared by asimilar method to that of Example 2, Footnote c (A), fromN-(3-hydroxyphenyl)acetamide, in Ph₂ O (100 ml) was heated at 250° C.for 10 minutes, cooled and diluted with hexane (100 ml) to givecrystals. The crystals were re-crystallised from ethyl acetate. Theliquors were evaporated and dissolved in 0.2M aqueous NaOH, filteredthough Celite, and acidified with 1M aqueous HCl solution to giveN-(4-allyl-3- hydroxyphenyl)acetamide (3.6 g) mpt. 164°-165° C.

The phenol was converted to N-(4-allyl-3-benzyloxyphenyl)acetamide by asimilar method to that of Example 1, (I).

The allyl compound and ethyl 4-iodobenzoate were converted to ethyl 4-3-(2-benzyloxy-4-acetylaminophenyl)prop-1-enyl!benzoate by a similarmethod to that of Example 19 (c).

The olefin was converted to ethyl 4-3-(2-benzyloxy-4-acetylaminophenyl)propyl!benzoate by a similar methodto that of Example 33, Footnote a.

EXAMPLE 41 4- 3-(2-Benzyloxy-4-benzenesulphonamidophenyl)propyl!benzoicacid

The title compound was prepared from ethyl 4-3-(2-benzyloxy-4-benzenesulphonamidophenyl)propyl!benzoate by a similarmethod to that of Example 1, (A).

The ethyl ester was prepared as follows:

To a solution of PCl₅ (1.25 g) and pyridine (1.13 ml) in CH₂ Cl₂ (50 ml)and -30° C. was added a solution of ethyl 4-3-(2-benzyloxy-4-acetylaminophenyl)propyl!benzoate (2.3 g) in CH₂ Cl₂(10 ml). The mixture was stirred at -20° C. for 30 minutes, ethanol (3.5ml) was added, and the mixture stirred for 30 minutes at -10° C. Water(50 ml) was added the mixture stirred for 30 minutes at ambienttemperature. The Layers were separated and the organic solution washedwith saturated aqueous NaHCO₃. The solvent was evaporated, the residuedissolved in diethyl ether and a solution of toluenesulphonic acidmonohydrate (500 mg) added in ethyl acetate (10 ml). Crystals of thetosic acid salt of ethyl 4- 3-(2-benzyloxy-4-aminophenyl)propyl!benzoatewere formed (0.4 g) mpt. 134°-140° C.

The aniline was converted to ethyl 4-3-(2-benzyloxy-4-benzenesulphonamidophenyl)propyl!benzoate by a similarprocedure to that of Example 3, Footnote g.

EXAMPLE 42 N-(4-Nitrophenylsulphonyl)-4-3-(2-benzyloxyphenyl),propyl!benzamide

A mixture of 4- 3-(2-benzyloxyphenyl)propyl)benzoic acid 0.2 g),4-nitrobenzenesulphonamide (0.12 g), DMAP (0.15 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) wasstirred for 65 hours. The mixture was diluted with EtOAc, washed withwater and brine, dried (MgSO₄), filtered and evaporated. The residue waspurified by flash chromatography on silica gel, eluting with ethylacetate, to give the title compound (0.21 g) mpt. 112°-113° C.

EXAMPLE 43 N-(Phenylsulphonyl)-4-3-(2-benzyloxy-5-chlorophenyl)propyl!benzamide

The title compound was synthesised from 4-3-(2-benzyloxy-5-chlorophenyl)propyl!benzoic acid by a similar method tothat of Example 42.

EXAMPLE 44 4-3-(2-Benzyloxyphenyl)propyl!-N-(2-pyridylmethyl)benzenecarboxamide.

Oxalyl chloride (3.27 g) was added dropwise to a stirred solution of 4-3-(2-benzyloxyphenyl)propyl!benzene carboxylic acid (6 g) in methylenechloride (100 ml) containing N,N-dimethylformamide (0.1 ml). Thereaction mixture was stirred at 22° C. for 16 hours, the solvent wasremoved and the residue issolved in methylene chloride (90 ml) .

The solution of the acid chloride in methylene chloride 15 ml)(described above) was added to a stirred solution of2-aminomethylpyridine (0.13 g) and triethylamine (0.87 g) in methylenechloride (15 ml) and the mixture was stirred at ambient temperature for2 hours. The reaction mixture was washed twice with water (20 ml eachtime) and dried over anhydrous magnesium sulphate. The residue obtainedon removal of the solvent was subjected to 'flash' chromotography onsilica (Merck 9385) eluting with a mixture of ethyl acetate anddichloromethane (1:1 v/v) to give 4-3-(2-benzyloxyphenyl)propyl!-N-2-(2-pyridylmethyl)benzenecarboxamide (mp70° C.; yield 48%).

EXAMPLE 45

The procedure outlined in example 44 was repeated using the appropriatecarboxylic acid and amine of R' to give the following:

    __________________________________________________________________________     ##STR70##                                                                    Compound                                                                            Ar         n R      R'            MP °C.                                                                        Footnote                       __________________________________________________________________________     1                                                                                   ##STR71## 3 H      NHC(Me).sub.2 CH.sub.2 OH                                                                    65                                    2    "          3 H      NHCH.sub.2 CH.sub.2 OH                                                                      112    a                               3    "          3 H                                                                                     ##STR72##     93                                    4    "          3 H      NHCH.sub.2 CH.sub.2 OMe                                                                     101                                    5    "          3 H      NHCH.sub.2 CH.sub.2 OMe                                                                      62-3                                  6                                                                                   ##STR73## 3 F      NHCH.sub.2 CH.sub.2 OH                                                                      107    a                               7    "          3 F      NHC(Me).sub.2 CH.sub.2 OH                            8    "          3 F                                                                                     ##STR74##     76                                    9    "          3 H                                                                                     ##STR75##     120-122                              10    "          3 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 74-7                                 11    "          2 H      NHCH.sub.2 CH.sub.2 OH                                                                      102-4  a                              12    "          2 H                                                                                     ##STR76##     89-90                                13    "          3 H                                                                                     ##STR77##    oil                                   14    "          2 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 93-4                                 15    "          3 H                                                                                     ##STR78##     79-81                                16    "          3 H      NHnBu          69                                   17    "          3 H      NHiPr         121-2                                 18    "          3 H      NHMe           109-110                              19    "          3 H                                                                                     ##STR79##     84                                   20    "          3 H                                                                                     ##STR80##     87                                   21    "          3 H                                                                                     ##STR81##    100-1                                 22    "          3 H                                                                                     ##STR82##    124-5                                 23    "          3 MeS    NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 92                                   24    "          2 NO.sub.2                                                                             NHCH.sub.2 CH.sub.2 OH                                                                      134-5                                 25    "          2 NO.sub.2                                                                              ##STR83##    117-8                                 26    "          2 NO.sub.2                                                                              ##STR84##    156-8                                 27    "          2 Br     NHCH.sub.2 CH.sub.2 OH                                                                      143-4                                 28    "          2 Br                                                                                    ##STR85##    123-4                                 29    "          2 Br                                                                                    ##STR86##    162-3                                 30    "          2 CN     NHCH.sub.2 CH.sub.2 OH                                                                      115-6                                 31    "          2 CN                                                                                    ##STR87##     129-30                               32    "          2 CN                                                                                    ##STR88##    160-1                                 33    "          3 Br     NHCH.sub.2 CH.sub.2 OH                                                                      112-3                                 34    "          3 Br                                                                                    ##STR89##    107-8                                 35    "          3 Br                                                                                    ##STR90##    130-1                                 36    "          3 CN     NHCH.sub.2 CH.sub.2 OH                                                                      132-3                                 37    "          3 CN                                                                                    ##STR91##    137-8                                 38    "          3 CN                                                                                    ##STR92##     110-111                              39    "          3 Cl                                                                                    ##STR93##       135-135.5                          40    "          3 Cl     NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 94.5-95.5                            41    "          3 H      NHEt          114-5                                 42    "          3 NO.sub.2                                                                             NHCH.sub.2 CH.sub.2 OH                                                                      127-9                                 43    "          3 NO.sub.2                                                                              ##STR94##     109-111                              44    "          3 NO.sub.2                                                                              ##STR95##     149-150                              45    "          3 CH.sub.3 CO                                                                          NHCH.sub.2 CH.sub.2 OH                                                                      115-7                                 46    "          3 CH.sub.3 CO                                                                           ##STR96##    155-6                                 47    "          3 CH.sub.3 CO                                                                           ##STR97##    135-7                                 48    "          3 CH.sub.3 CO                                                                          NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 109-110                              49    "          3 H      NHCH.sub.2 CH.sub.2 NH.sub.2                                                                110                                   50    "          3 H      NHCH.sub.2 CH.sub.2 NHCOMe                                                                   147-149                              51    "          3 H      NHCH.sub.2 COOEt                                                                            Gum                                   52    "          3 H      NHCH.sub.2 CH.sub.2 COOEt                                                                   Gum                                   53    "          3 H                                                                                     ##STR98##    255                                   54    "          3 H                                                                                     ##STR99##     84                                   55    "          3 H                                                                                     ##STR100##    87                                   56    "          3 H                                                                                     ##STR101##   104                                   57    "          3 SMe                                                                                   ##STR102##   124                                   58    "          3 SMe                                                                                   ##STR103##   105                                   59    "          3 SMe                                                                                   ##STR104##   123                                   60    "          3 SO.sub.2 Me                                                                          NHCH.sub.2 CH.sub.2 OH                                                                       129-130                              61    "          3 SO.sub.2 Me                                                                           ##STR105##    146-148                              62    "          3 SO.sub.2 Me                                                                           ##STR106##    158-159                              63    "          3 H                                                                                     ##STR107##   --                                    64    "          3 H      NHCH.sub.2 CF.sub.2 CF.sub.3                                                                110                                   65    "          3 H                                                                                     ##STR108##    83-85                                66    "          3 H                                                                                     ##STR109##    95-98                                67    "          3 H                                                                                     ##STR110##    74-78                                68    "          4 H                                                                                     ##STR111##    71                                   69    "          4 H      NHCH.sub.2 CH.sub.2 OH                                                                       52                                   70    "          4 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 54                                   71    "          3 H                                                                                     ##STR112##   106                                   72                                                                                   ##STR113##                                                                              3 H      NHCH.sub.2 CH.sub.2 OH                                                                      --                                    73    "          3 H                                                                                     ##STR114##   --                                    74                                                                                   ##STR115##                                                                              2 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 96-97                                75    "          2 H                                                                                     ##STR116##    69-70                                76    "          2 H                                                                                     ##STR117##    88-89                                77    "          2 H      NHCH.sub.3     111-112                              78    "          2 Br     NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 102-103                              79    "          2 Br                                                                                    ##STR118##    95-98                                80    "          2 Br     NHCH.sub.2 CH.sub.2 OH                                                                       96-98                                81    "          2 Br                                                                                    ##STR119##    159-160                              82    "          3 H      NHCH.sub.2 CH.sub.2 OH                                                                       101-102                              83    "          3 H                                                                                     ##STR120##   --                                    84    "          3 H                                                                                     ##STR121##   --                                    85    "          3 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                --                                    86                                                                                   ##STR122##                                                                              3 H      NHCH.sub.2 CH.sub.2 OH                                                                      112                                   87    "          3 H                                                                                     ##STR123##   --                                    88    "          3 H                                                                                     ##STR124##   --                                    89                                                                                   ##STR125##                                                                              3 H                                                                                     ##STR126##    134-135                              90    "          3 H      NHCH.sub.2 CH.sub.2 SEt                                                                      63-65                                91    "          3 H      NHCH.sub.2 CN  100-102                              92                                                                                   ##STR127##                                                                              3 H      NHCH.sub.2 CH.sub.2 OH                                                                      --                                    93    "          3 H                                                                                     ##STR128##   --                                    94                                                                                   ##STR129##                                                                              2 H      NHCH.sub.2 CH.sub.2 OH                                                                       128-129                              95    "          2 H                                                                                     ##STR130##    114-115                              96    "          2 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 112-115                              97                                                                                   ##STR131##                                                                              3 H                                                                                     ##STR132##    66-69                                98    "          3 H                                                                                     ##STR133##    93-94                                99                                                                                   ##STR134##                                                                              2 H                                                                                     ##STR135##    95-99                                100   "          2 H      NHCH.sub.2 CH.sub.2 OH                                                                       133-134                              101   "          2 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 68-72                                102   "          3 H                                                                                     ##STR136##   --                                    103   "          2 H                                                                                     ##STR137##    175-176                              104                                                                                  ##STR138##                                                                              3 H      NHCH.sub.2 CH.sub.2 CH.sub.2 OH                                                              75-79                                105                                                                                  ##STR139##                                                                              3 H                                                                                     ##STR140##    78-80                                106   "          3 H      NHCH.sub.2 CH.sub.2 OH                                                                       79-83                                107   "          3 H      NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 71-74                                108   "          2 Br                                                                                    ##STR141##    195-197                              109   "          2 Br     NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 140-144                              110   "          2 Br     NHCH.sub.2 CH.sub.2 OH                                                                       139-143                              111                                                                                  ##STR142##                                                                              2 H                                                                                     ##STR143##   --                                    112                                                                                  ##STR144##                                                                              3 H      "              108-111                              113                                                                                  ##STR145##                                                                              2 SMe    NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 108-110                              114   "          2 SMe    NHCH.sub.2 CH.sub.2 OH                                                                       110-112                              115   "          2 SMe                                                                                   ##STR146##    54-56                                116   "          2 SO.sub.2 Me                                                                           ##STR147##    184-186                              117   "          2 Br                                                                                    ##STR148##    137-139                              118   "          2 SO.sub.2 Me                                                                          NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 167-168                              119                                                                                  ##STR149##                                                                              2 Br                                                                                    ##STR150##    227-229                              120                                                                                  ##STR151##                                                                              2 Br     NHCH.sub.2 CN  226-228                              121                                                                                  ##STR152##                                                                              2 Br     NHCH.sub.2 CN  132-134                              122   "          2 Br     NHCH.sub.2 CH.sub.2 CH.sub.3                                                                 68-70                                123   "          2 Br     NHCH.sub.2 CH.sub.2 OH                                                                       106-108                              124   "          2 Br                                                                                    ##STR153##    135-137                              125   "          2 Br                                                                                    ##STR154##    76-78                                126                                                                                  ##STR155##                                                                              2 Br                                                                                    ##STR156##    250-253                              127                                                                                  ##STR157##                                                                              3 CH.sub.2 OMe                                                                         NHCH.sub.2 CH.sub.2 CH.sub.3                                                                  81.5-84                             128   "          3                                                                                ##STR158##                                                                          NHCH.sub.2 CH.sub.2 CH.sub.3                                                                   130-131.5                          129   "          3 H      NEt.sub.2     Oil                                   130   "          3 H      NH.sub.2       133-134                              131   "          3 NO.sub.2                                                                             NH.sub.2       168-169                              132   "          3 NO.sub.2                                                                              ##STR159##    149-150                              __________________________________________________________________________

EXAMPLE 46

The procedure outlined in example 44 was repeated using the appropriatecarboxylic acid and amine to give the following:

    __________________________________________________________________________     ##STR160##                                                                   Compound                                                                            R   X     Ar      R1        mpt                                         __________________________________________________________________________    1     H   (E)CHCH                                                                              ##STR161##                                                                            ##STR162##                                                                             159-161                                     2     H   (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 CH.sub.3                                                              126-127                                     3     H   (E)CHCH                                                                             "                                                                                      ##STR163##                                                                             120-122                                     4     5-Br                                                                              (E)CHCH                                                                             "       "         144-148                                     5     5-Br                                                                              (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 OH                                                                    151-153                                     6     5-SMe                                                                             (E)CHCH                                                                             "                                                                                      ##STR164##                                                                             120-122                                     7     5-SMe                                                                             (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 CH.sub.3                                                              144-147                                     8     5-SMe                                                                             (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 OH                                                                    125-128                                     __________________________________________________________________________

EXAMPLE 47 4-3-(2-Benzyloxy-5-methylthiophenyl)propyl!-N-(2-hydroxyethyl)benzenecarboxamide

(A) A mixture of methyl 4-3-(2-benzyloxy-5-methylthiophenyl)-propyl!benzoate (0.55 g) and2-aminoethanol (0.24 g) was stirred and heated at 140° C. for 2 hours.The cooled reaction mixture was subjected to chromatography on silica(Merck type 9385) eluting with ethyl actate. The required fractions wereevaporated to dryness and the residue was triturated with diethyl etherto give 4-3-(2-benzyloxy-5-methylthio)propyl!-N-(2-hydroxyethyl)benzenecarboxamidehemihydrate (mp 110°-112° C.; yield 53%)

The starting material was prepared as follows:

(B) The 4- 3-(2-benzyloxy-4-methylthio)propyl!-benzenecarboxylic acidwas prepared from the corresponding2-benzyloxy-4-methylthiobenzaldehyde. The2-benzyloxy-4-methylthiobenzaldehyde was prepared by standard means from2-hydroxy-4-methylthiobenzaldehyde, the preparation of which isdescribed in Bull. Chem. Soc. Jap. 51 2435 1968.

EXAMPLE 48 4-3-(2-Benzyloxy-5-methylsulphinylphenyl)propyl!-N-(2-hydroxyethyl)benzenecarboxamide

A slurry of 4-3-(2-benzyloxy-5-methylthiophenyl)-propyl!-N-(2-hydroxyethyl)benzenecarboxamide(0.22 g) in methanol (10 ml) was added to a stirred solution of sodiummetaperiodate (0.113 g) in water (1 ml) maintained at 0° C. by externalcooling. The reaction mixture was stirred at 0° C. for 2 hours, thenconcentrated to a volume of approximately 2 ml. This residue wasdissolved in ethyl acetate (10 ml), the ethyl acetate solution was dried(anhydrous magnesium sulphate) and the solution evaporated to dryness.The residue was subjected to chromatography on silica (Merck) elutedwith a mixture of methanol/ethyl acetate (1:9 v/v). The only porductobtained was triturated with ethyl acetate (2 ml) to give 4-3-(2-benzyloxy-5-methylsulphinylphenyl)propyl!-N-(2-hydroxyethyl)-benzenecarboxamide(mp. 105°-108° C.; 43% yield).

EXAMPLE 49 4-3-(2-Benzyloxy-5-methylsulphonylphenyl)propyl!-N-propylbenzenecarboxamide

A mixture of 4-3-(2-benzyloxy-5-methylthiophenyl)propyl!-N-propylbenzenecarboxamide(0.7 g) and metachloroperbenzoic acid (1.22 g) in methylene chloride (20ml) was stirred at ambient temperature for 18 hours. The reactionmixture was washed four times with saturated aqueous sodium bicarbonatesolution (20 ml each time), dried and evaporated to dryness. The residuewas subjected to chromatography on silica (Merck 9385), eluting with amixture of ethyl acetate and methylene chloride (1:9 v/v) to give 4-3-(2-benzyloxy-5-methylsulphonylphenyl)propyl!-N-propylbenzenecarboxamide(mp. 121°-122 0° C.; yield 29%).

EXAMPLE 50 4-3-(5-Amino-2-benzyloxyphenyl)ethyl!-N-(2-hydroxyethyl)benzenecarboxamide

A mixture of 4-3-(2-benzyloxy-5-nitrophenyl)ethyl!-N-(2-hydroxyethyl)benzenecarboxamide(0.5 g) and stannous chloride dihydrate (2.15 g) in ethanol (50 ml) washeated at 70° C. for 4 hours, and then stirred at ambient temperaturefor 16 hours. The reaction mixture was poured onto crushed ice and thepH adjusted to 8 with saturated aqueous sodium bicarbonate solution. Thebasic aqueous solution was extracted three times with ethyl acetate (50ml each time) and the extracts were dried (MgSO₄). The solid obtained onremoval of the solvent was subjected to 'flash' chromatography on silica(Merck 9385) eluting with ethyl acetate initially then a mixture ofmethanol and ethyl acetate (1:9 v/v) to give 4-3-(5-amino-2-benzyloxyphenyl)ethyl!-N-(2-hydroxyethyl)benzenecarboxamide(mp. 127°-8° C.; yield 65%).

EXAMPLE 51

The procedure outlined in Example 50 was repeated using the appropriate4- 3-(2-benzyloxy-5-nitrophenyl)alkyl!-N-substituted benzene-carboxamideto give:

    ______________________________________                                         ##STR165##                                                                   Compound                                                                              n      R              m.p    Footnote                                 ______________________________________                                        1       2                                                                                     ##STR166##    127-8  a                                        2       2                                                                                     ##STR167##    52-4   b                                        3       3      CH.sub.2 CH.sub.2 OH                                                                         79-82  c                                        4       3                                                                                     ##STR168##    52-3   d                                        5       3                                                                                     ##STR169##    118-9  e                                        6       3      H              86-87                                           ______________________________________                                         Footnotes                                                                     (a) Prepared from example 45 compound 25.                                     (b) Prepared from example 45 compound 26.                                     (c) Prepared from example 45 compound 42.                                     (d) Prepared from example 45 compound 43.                                     (e) Prepared from example 45 compound 44.                                

EXAMPLE 52 4-3-(2-Benzyloxy-5-(1-hydroxyiminoethyl)phenyl)propyl!-N-(2-hydroxyethyl)-benzenecarboxamide

A mixture of 4-3-(5-acetyl-2-benzyloxyphenyl)propyl!-N-(2-hydroxyethyl)benzenecarboxamide(0.5 g) (example 2, compound 45) hydroxylamine hydrochloride (0.16 g) inpyridine (5 ml) was heated at 60° C. for 2 hours. The pyridine wasremoved and the residue subjected to flash chromatography on silica,eluting with a mixture of ethyl acetate/hexane (4:1 v/v) to yield in theappropriate fractions, 4-3-(2-benzyloxy-5-(1-hydroxyiminoethyl)phenyl)propyl!-N-(2-hydroxyethyl)benzenecarboxamide(m.p. 131°-2° C.; yield 56%).

EXAMPLE 53

The procedure outlined in example 52 was repeated using the appropriate4- 3-(5-acetyl-2-benzyloxyphenyl)propyl!-N-substitutedbenzenecarboxamide to give:

    ______________________________________                                         ##STR170##                                                                   Compound                                                                              R              M.p. °C.                                                                        Starting material                             ______________________________________                                                 ##STR171##    170-20   Example 45, compound 47                       2                                                                                      ##STR172##    139-141                                                3       Pr.sup.n       140-141  Example 45, compound 48                       ______________________________________                                    

EXAMPLE 54 4-3-(2-Benzyloxyphenyl)propyl!-N-(4-imidazolyl)-2-ethyl)benzenecarboxamide

A mixture of 4- 3-(2-benzyloxyphenyl)propyl!-benzene-carboxylic acid(13.7 g), diphenylphosphoryl azide (10.9 g) and triethylamine (28 ml) inmethylene chloride (500 ml) was stirred at ambient temperature for 1hour. Solid histamine dihydrochloride was added and the reaction mixturewas stirred for 16 hours. The reaction mixture was washed three timeseach with water (100 ml each time) and 2N sodium hydroxide solution (100ml each time) and dried. The residue obtained on evaporation of thesolvent was subjected to chromatography on silica, eluting with ethylacetate and then with an ethyl acetate/methanol mixture (4:1 v/v).Concentration of the appropriate fractions yielded 4-3-(2-benzyloxyphenyl)-propyl-N-(4-(imidazolyl)-2-ethyl)benzenecarboxamidem.p. 124-5; yield 3.6 g (20%)!.

EXAMPLE 55 (E)-4-2-(2-Benzyloxyphenyl)ethenyl!-N-(2-hydroxyethyl)benzenecarboxamide

(A) A solution of 4- 2-(2-benzyloxyphenyl)ethenyl!-benzenecarbonylchloride (0.98 g) in dichloromethane (5 ml) was added dropwise to asolution of 2-aminoethanol (0.51 ml) in dichloromethane (15 ml)maintained at 0° C. The reaction mixture was allowed to warm to ambienttemperature and was stirred for 16 hours. The reaction mixture waswashed with water (20 ml) and saturated aqueous sodium bicarbonate (20ml) and dried. Evaporation of the solvent left a solid residue which wascrystallised twice from methanol to give (E)-4-2-(2-benzyloxyphenyl)ethenyl!-N-(2-hydroxyethyl)benzenecarboxamide (m.p.149°-151° C.; yield 19%) containing about 4% of the related Z-isomer.

(B) The methanol filtrates from the crystallisation described above werecombined and evaporated to dryness to give a 5:1 mixture of Z:E4-{2-(2-benzyloxyphenyl)ethenyl!-N-(2-hydroxyethylbenzene-carboxamide(m.p. 87-93° C.; yield 38%).

(C) Using the same procedure with 2-aminomethylpyridine as the aminecomponent there was obtained 4-2-(2-benzyloxyphenyl)ethenyl!-N-(2-pyridylmethyl)benzene carboxamide asa 13:1 mixture of E:Z isomers (m.p. 123°-127°; yield 18%) and 4-2-(2-benzyloxyphenyl)ethenyl!-N-(2-pyridylmethyl)benzene carboxamide asa 7:1 mixture of Z:E isomers as a viscous gum (yield 21%).

(D) The 4- 2-(2-benzyloxyphenyl)ethenyl!benzenecarbonyl chloride used asstarting material was prepared from the corresponding carboxylic acidand oxalyl chloride as described in example 1 and was used withoutfurther purification.

EXAMPLE 56 4-3-(2-Benzyloxyphenyl)propyl!-N-(2-pyridylmethylcarbonyl)benzamine

(A) Diphenylphosphoryl azide (0.46 ml) was added dropwise to a stirredsuspension of 2-pyridylacetic acid (0.367 g) and triethylamine (0.3 ml)in N,N-dimethylformamide (10 ml) maintained at 0° C. A suspension of 4-3-(2-benzyloxyphenyl)propyl!benzeneamine hydrochloride (0.75 g) inN,N-dimethylformamide (10 ml) containing triethylamine (0.9 ml) wasadded rapidly to the reaction mixture. Stirring was continued at ambienttemperature for 16 hours and the reaction mixture was concentrated tosmall volume. The residue was partitioned between water and diethylether. The diethyl ether extract was washed once each with saturatedaqueous sodium bicarbonate (20 ml) and brine (20 ml) and dried. The gumobtained on removal of the solvent was subjected to chromatography onsilica (Merck 9385) eluted with a mixture of ethyl acetate and hexane(1:1 v/v). The gum obtained was triturated with ether at 0° C. to give4- 3-(2-benzyloxy-phenyl)propyl!-N-(2-pyridylmethylcarbonyl)benzeneamine(m.p. 61°-2° C.; yield 0.63 g 68%).

(B) In the like manner using the appropriate carboxylic acid there wasprepared 4-3-(2-benzyloxyphenyl)propyl!-N-(3-pyridylmethylcarbonyl)benzeneamine(m.p. 99°-100° C.; yield 0.90 g 72%).

The 4- 3-(2-benzyloxyphenyl)propyl!benzeneamine used as startingmaterial was prepared as follows:

(C) A mixture of 4- 3-(2-benzyloxyphenyl)propyl!benzene carboxylic acid(8.39 g), diphenylphosphoryl azide (5.74 ml) and triethylamine (7.1 ml)in t-butanol (80 ml) was heated under reflux in an argon atmosphere for16 hours. The reaction mixture was evaporated to dryness and the residuepartitoned between ethyl acetate and water. The ethyl acetate extractwas washed once each with 2N HCl, water, saturated aqueous sodiumbicarbonate solution and brine (20 ml each time) and dried (MgSO4). Thesolvent was evaporated and the residue subjected to flash chromatographyeluted with a mixture of dichloromethane:hexane (1:1 v/v) to give Nt-butyloxycarbonyl-4-{3-(2-benzyloxyphenyl)propyl!benzene-amine 7.69 gm.p. 86°-8° C. which was used directly in the next step.

(D) A solution of N-t-butoxycarbonyl-4-3-(2-benzyloxyphenyl)-propyl!benzeneamine in chloroform (50 ml) wastreated with trimethyl-silyl iodide (3.8 ml) at 0° C. and then stirredat ambient temperature for 10 minutes. The solvent was concentrated andthe oily residue was dissolved in diethyl ether and washed consecutivelywith saturated aqueous sodium bicarbonate (50 ml) and water (50 ml). Thediethyl ether solution was shaken with 3N aqueous HCl and the 4-3-(2-benzyloxphenyl)propyl!benzeneamine hydrochloride was collected.Yield=5.94 g (91%).

EXAMPLE 57 4-3-(2-Benzyloxyphenyl)propyl!-N-(3-methoxypropionyl)-benzeneamine

Oxalyl chloride (0.41 ml) was added to a stirred solution of3-methoxypropanoic acid (0.45 ml) in methylene chloride (15 ml)containing 1 drop of N,N-dimethylformamide. The mixture was stirred atambient temperature for 3 hours. A 5 ml aliquot of this reaction mixturewas added dropwise to a solution of 4-3-(2-benzyloxyphenyl)-propyl!-benzeneamine hydrochloride (0.63 g) indichloromethane (20 ml) containing triethylamine (0.82 ml). Stirring wascontainued for 16 hours. The reaction mixture was evaporated to drynessand the residue was partitioned between diethyl ether and water. Thediethyl ether extract was washed consecutively with aqueous 2N HCl (20ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml) thendried (MgSO₄). The residue obtained on removal of the solvent wassubjected to flash chromatography on silica (Merck 9385) eluted withether, to give, after crystallisation from diethyl ether-hexane mixture,4- 3-(2-benzyloxyphenyl)propyl!-N-(3-methoxypropionyl)-benzeneamine,m.p. 65°-6° C., yield 0.58 g (80%).

EXAMPLE 58

Using the procedure described in example 57 and the appropriate acid(RCO₂ H) and 4- 3-(2-benzyloxyphenyl)propyl!benzeneamine hydrochloridethere was prepared:

    ______________________________________                                         ##STR173##                                                                   Compound                                                                              R                pt        Footnote                                   ______________________________________                                                 ##STR174##      119-121                                              2       nPr              98-99                                                3       CH.sub.2 CH.sub.2 CO.sub.2 H                                                                   138-139   a                                          4                                                                                      ##STR175##      174-177   b                                          ______________________________________                                         Notes                                                                         (a): Mono-methylsuccinate was used to prepare the intermediate                N(4-(3-(2-benzyloxyphenyl)propyl)phenyl!-2-(methoxycarbonyl)propionam ide     This was hydrolysed to the corresponding carboxylic acid using a similar      method to that of Example 1 (A).                                              (b): The acid component was coupled to the benzeneamine using a similar       method to that of Example 71.                                            

EXAMPLE 59 4- 3-(2-benzyloxyphenyl)propyl!-N- 3-hydroxypropionyl!benzeneamine

Propiolactone (0.23 ml) was added to a mixture of 4-3-(2-benzyloxyphenyl!propyl!benzeneamine hydrochloride (1.26 g) andtriethylamine (0.5 ml) in methylene chloride (10 ml) and the mixture wasstirred for 18 hours. A further equivalent of propiolactone (0.23 ml)was added and stirring continued for a further 24 hours. The reactionmixture was concentrated and the residue was subjected to flashchromatography on silica eluted with a stepwise gradient of methanol inmethylene chloride. The fractions eluting with 5% methanol in methylenechloride were collected, concentrated and subjected to chromatographyagain, eluting with ethyl acetate to give, after crystallisation fromdichloromethane/hexane (1:20 v/v) 4-3-(2-benzyloxyphenyl)propyl!-N-(3-hydroxypropionyl!benzene amine m.p.109°-110°, 0.22 g (15%).

EXAMPLE 60

A similar procedure to that outlined in example 47 was repeated with theappropriate carboxylic ester and amine to give the compounds listed inthe table. Reactions with ethanolamine were carried out neat. Ethanolwas used as a solvent for other amines.

    __________________________________________________________________________     ##STR176##                                                                   Compound                                                                            Ar      n R  R.sup.1   mpt .sup.° C.                                                               footnote                                    __________________________________________________________________________     1                                                                                   ##STR177##                                                                           2 H  CH.sub.2 CH.sub.2 OH                                                                    169-170                                                                            a                                            2    "       2 H                                                                                 ##STR178##                                                                             121-124                                           3                                                                                   ##STR179##                                                                           2 H  CH.sub.2 CH.sub.2 CH.sub.3                                                              79-80                                             4    "       2 H                                                                                 ##STR180##                                                                             72-74                                             5    "       2 H                                                                                 ##STR181##                                                                             138-139                                           6                                                                                   ##STR182##                                                                           2 H  CH.sub.2 CH.sub.2 OH                                                                    101-102                                           7    "       2 H                                                                                 ##STR183##                                                                             133-134                                           8    "       2 H                                                                                 ##STR184##                                                                             174-175                                           9    "       2 H  CH.sub.3  114-115                                          10                                                                                   ##STR185##                                                                           2 H  CH.sub.2 CH.sub.2 OH                                                                    64-66                                            11                                                                                   ##STR186##                                                                           2 Br CH.sub.2 CH.sub.2 CH.sub.3                                                              82-83                                            12    "       2 Br CH.sub.2 CH.sub.2 OH                                                                    138-139                                          13                                                                                   ##STR187##                                                                           2 Br                                                                                ##STR188##                                                                             175-176                                          14    "       2 Br                                                                                ##STR189##                                                                             197-198                                          15    "       3 H  CH.sub.2 CH.sub.2 CH.sub.3                                                              64-65                                            16    "       3 H  CH.sub.2 CH.sub.2 OH                                                                    101-102                                          17    "       3 H                                                                                 ##STR190##                                                                             91-92                                            18    "       2 SMe                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                              59-60                                            19    "       2 SMe                                                                               ##STR191##                                                                             150-151                                          20    "       2 SMe                                                                               ##STR192##                                                                             174-176                                          __________________________________________________________________________    Footnotes                                                                     a: A mixture of methyl 3-(2-benzyloxyphenyl)propionate (2.95 g; and           hydrazine                                                                     hydrate (1.0 ml) was heated at refulx in ethanol (30 ml) for 24 hours.        The                                                                           mixture was cooled and a solid crystallised (1.82 g). The solid (1.0 g)       and                                                                           ethyl aminothioxoacetate (0.5 g) were heated together at 120° C.       for                                                                           15 minutes under reduced pressure to give a white solid (0.74 g) after        washing                                                                       with ethanol. This material was heated at 210° C. for 15 minutes       to give                                                                       ethyl 5- 2-benzyloxyphenethyl!-1,2,4-triazol-3-ylcarboxylate (0.41 g)         after                                                                         purification be flash chromatography, eluting with diethyl ether.         

EXAMPLE 61

N-Propyl-4- 3-(2-benzyloxy-5-methanesulphinylphenyl)propyl!benzamide wasprepared by oxidising the corresponding methylthio compound (compound23, Example 45) using a similar method to that described in footnote uof Example 3 mpt. 101°-102° C.

EXAMPLE 62

N-Cyclopropyl-4-3-(2-benzyloxy-5-methanesulphinylphenyl)propyl!benzamide was prepared byoxidising the corresponding methylthio compound (compound 58, example45) using a similar method to that described in footnote u of example 2mpt. 107°-108° C.

EXAMPLE 63

The processes described in example 56 were repeated using theappropriate carboxylic acids to give the following:

    __________________________________________________________________________     ##STR193##                                                                   Compound                                                                            R   X     Ar         R.sup.1   mpt .sup.° C.                     __________________________________________________________________________    1     H   (E)CHCH                                                                              ##STR194##                                                                               ##STR195##                                                                             142-145                                  2     H   CH.sub.2 CH.sub.2                                                                   "          "         160-162                                  3     5-NO.sub.2                                                                        (CH.sub.2).sub.3                                                                     ##STR196##                                                                              "         155-156                                  __________________________________________________________________________

EXAMPLE 64

The process described in example 54 was repeated using the appropriatecarboxylic acids and amines to give the follow:

    __________________________________________________________________________     ##STR197##                                                                   Compound                                                                            R    X   Ar      R.sup.1    mpt (.sup.o C)                              __________________________________________________________________________    1     5-SOMe                                                                             (CH.sub.2).sub.3                                                                   ##STR198##                                                                            ##STR199##                                                                              136-137                                     2     5-SOMe                                                                             (CH.sub.2).sub.3                                                                  "                                                                                      ##STR200##                                                                              138                                         3     H    (CH.sub.2).sub.3                                                                  "                                                                                      ##STR201##                                            4     H    (CH.sub.2).sub.3                                                                   ##STR202##                                                                           CH.sub.2 CH.sub.2 OH                                   5     H    (CH.sub.2).sub.3                                                                  "       CH.sub.2 CH.sub.2 CH.sub.3                                                               66-68                                       6     H    (CH.sub.2).sub.3                                                                  "                                                                                      ##STR203##                                                                              75-80                                       7     6-OH (CH.sub.2).sub.3                                                                   ##STR204##                                                                           "          172-174                                     8     6-OH (CH.sub.2).sub.3                                                                  "       CH.sub.2 CH.sub.2 OH                                                                     105                                         __________________________________________________________________________

EXAMPLE 65 N-(2Hydroxyethyl)-N-methyl-4-3-(2-benzyloxphenyl)propyl!benzamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g) wasadded to a mixture of 4- 3-(2-benzyloxyphenyl)propyl!benzene carboxylicacid (2 g) and triethylamine (1.75 g) in methylene chloride (20 ml). Thereaction mixture was stirred for 20 minutes at 20° C., and2-methylaminoethanol (0.86 g) was added. The reaction mixture wasstirred at 20° C. for 16 hours, washed with water (50 ml) and dried(MgSO₄). The residue obtained on removal of solvent was subjected to'flash' chromatography on silica, eluting with ethyl acetate to giveN-(2-hydroxyethyl)-N-methyl-4- 3-(2-benzyloxyphenyl)propyl!benzamide asa gum (yield 19%).

EXAMPLE 66 N-(2-Chloroethyl)-4-(3-(2-benzyloxyphenyl)propyl!benzamide

A similar process to that of Example 2, Footnote c (C), was repeatedwith example 53 compound 2 to giveN-(2-chloroethyl)-4-(3-(2-benzyloxyphenyl)propyl!benzamide.

EXAMPLE 67 2-(3- 4-(3-(2-Benzyloxyphenyl)propyl)phenyl!ureido)ethanol

A similar process to that of Example 64 (C) was repeated, except thatthe t-butanol was replaced by ethanolamine, to give 2-(3-4-(3-(2-benzyloxyphenyl)propyl)phenyl!ureido)ethanol.

EXAMPLE 68

A similar procedure to that outlined in Example 54 was repeated usingcompound 19 from Example 28 and the appropriate amine to give thefollowing: ##STR205##

EXAMPLE 69 1,3-Dimethyl-4- 2-(4-3-(2-benzyloxyphenyl)propyl!benzylamino)ethyl!imidazolium iodide

A mixture of N- 2-(imidazol-4-yl)ethyl!-4-3-(2-benzyloxyphenyl)propyl!benzamide (2.2 g) iodomethane (0.71 g) andpotassium carbonate (1.38 g) were stirred in DMF (10 ml) for 18 hours. Afurther quantity of iodomethane (0.3 g) was added and the mixture wasstirred for 18 hours. The solvent was evaporated and the residuepurified by subjecting to chromatography on silica, eluting withmethanol: CH₂ Cl₂ (72:25), to give 1,3-dimethyl-4- 2-(4-3-(2-benzyloxyphenyl)propyl!benzylamino)ethyl!imidazolium iodide as agum (1.4 g).

EXAMPLE 70 1-Ethyl-3- 2-(4-3-(2-benzyloxyphenyl)propyl!benzylamino)ethyl!pyridinium iodide

A mixture of N-(2-(3-pyridyl)ethyl)-4- 3-(2-benzyloxyphenyl)propyl!benzamide(1 g) and ethyl iodide (0.54 g) was stirred in DMF (5ml) at 100° C. for 4 hours. The solvent was evaporated and the residuecrystallised from ethyl acetate to give 1-ethyl-3- 2-(4-3-(2-benzyloxyphenyl)propyl!benzylamino)ethyl!pyridinium iodide (463mg); mpt 89° C.

EXAMPLE 71 N-Methyl-N-hydroxy-4-(3-(2-benzyloxyphenyl)propyl)benzamide

A mixture of 4-(3-(2-benzyloxyphenyl)propyl!benzoic acid (1.0 g), 1-HOBT(0.39 g) and DCCI (0.595 g) in DMF (10 ml) was stirred for 3 hours, thenadded to a solution of N-methylhydroxylamine HCl (0.24 g) and Et₃ N(0.29 g) in CH₂ Cl₂ (10 ml) and stirred for 70 hours. The product wasextracted in 2N aqueous KOH and washed with ethyl acetate. The aqueoussolution was acidified with concentrated HCl and extracted with diethylether. The solvent was evaporated and the residue subjected to flashchromatography on silica gel (using diethyl ether:methanol (95:5) aseluant) to giveN-methyl-N-hydroxy-4-(3-(2-benzyloxyphenyl)propyl)benzamide as a gum(0.39 g).

EXAMPLE 72 N-Hydroxy-4-(3-(2-benzyloxyphenyl)propyl)benzamide

The procedure described in Example 71 was repeated using hydroxylaminehydrochloride to giveN-hydroxy-4-(3-(2-benzyloxyphenyl)propyl)benzamide. mpt. 103°-104° C.

EXAMPLE 73 1- 4-(3-(2-Benzyloxyphenyl)propyl)phenyl!-3-2-chloroethyl!urea

2-Chloroethyl isocyanate (0.35 ml) was added dropwise to a stirredsolution of 4- 3-(2-benzyloxyphenyl)propyl!benzamine (1.17 g) in CH₂ Cl₂(20 ml). After 30 minutes, the reaction mixture was evaporated to give ayellow gum which was subjected to medium pressure chromatography onsilica gel, eluting with CH₂ Cl₂ :diethyl ether (3:1), to give, aftercrystallisation from diethyl ether, 1-4-(3-(2-benzyloxyphenyl)propyl)phenyl!-3- 2-chloroethyl!urea (1.23 g);mpt 120°-121° C.

EXAMPLE 74

The procedure described in example 73 was repeated using the appropriateisocyanate (RNCO) and 'benzeneamine', to give the following compounds:

    ______________________________________                                         ##STR206##                                                                   Compound   R           mpt (°C.)                                                                       Footnote                                      ______________________________________                                        1          CH.sub.2 CO.sub.2 Et                                                                      111-112                                                2          CH.sub.2 CO.sub.2 H                                                                       184-185  a                                             ______________________________________                                         Footnote                                                                      a: Compound 2 was prepared from compound 1 using method Example 1 (A).   

EXAMPLE 75

(A) 4- 3-(2-Benzyloxyphenyl)propyl!benzene isocyanate in dioxane (1/3 ofthe solution that was prepared as described in (B) below) was added to astirred solution of 2-aminomethylpyridine (0.2 ml) in dichloromethane(10 ml) for 1 hour, evaporated to dryness and subjected to mediumpressure chromatography on silica gel to give, after crystallisationfrom diethyl ether, 1- 4-(3-(2-benzyloxyphenyl)propyl)phenyl!-3-2-pyridylmethyl!urea (0.62 g) mpt 126°-127° C.

(B) The solution of 4- 3-(2-benzyloxyphenyl)propyl!benzene isocyanate indioxane was prepared by heating a mixture of 4-3-(2-benzyloxyphenyl)propyl!benzoic acid (2.0 g), Et₃ N (1.61 ml) andDPPA (1.31 ml) in dioxane (20 ml) for 3 hours.

EXAMPLE 76

The procedure described in example 75 was repeated using the appropriateamines (RNH₂) and 4- 3-(2-benzyloxyphenyl)propyl!benzene isocyanate.

    ______________________________________                                         ##STR207##                                                                   Compound     R             mpt (°C.)                                   ______________________________________                                                      ##STR208##   132-133                                            2            CH.sub.2 CH.sub.2 CH.sub.3                                                                  90-91                                              ______________________________________                                    

EXAMPLE 77

A similar procedure to that of Example 72 (C) was repeated using theappropriate alcohol and modified by the addition of dioxane to give thefollowing carbamate compounds.

    ______________________________________                                         ##STR209##                                                                   Compound      R           mpt (°C.)                                    ______________________________________                                                       ##STR210##  96-97                                              2             CH.sub.2 CH.sub.2 OMe                                                                      45-47                                              ______________________________________                                    

EXAMPLE 78N-(4-(3-(5-Amino-2-benzyloxyphenyl)propyl)phenyl)-3-pyridineacetamide

The title compound was prepared from Compound 3, Example 71 using asimilar method to that of Example 2, Footnote a, mpt 110°-112° C.

EXAMPLE 79 N-4-(3-(5-Acetylamino-2-benzyloxyphenyl)propyl)phenyl!-3-(pyridyl)acetamid

The title compound was prepared from Example 78, using a similar methodto that of Example 2 Footnote b; mpt 172°-174° C.

EXAMPLE 80N-(4-(3-(5-(2-Methyl-2-hydroxypropionylamino)-2-benzyloxyphenyl)-propyl)phenyl)-3-pyridineacetamide

The title compound was prepared from Example 78, using a similar methodto that of Example 56 (A).

EXAMPLE 81 N-(2-(Ethanesulphinyl)ethyl)-4-3-(2-benzyloxyphenyl)propyl!benzamide

The title compound was prepared from Example 45 compound 90, using asimilar method to that of Example 56.

EXAMPLE 82 N-(2-(Ethanesulphonyl)ethyl)-4-3-(2-benzyloxyphenyl)propyl!benzamide

The title compound was prepared from Example 45 compound 90, using asimilar method to that of Example 57.

EXAMPLE 83 N-(Tetrazol-5-ylmethyl)-4-3-(2-benzyloxyphenyl)propyl!benzamide

The title compound was prepared from Example 45, compound 91 using asimilar method to that of Example 92 (A).

EXAMPLE 84 6- 2-(2-Benzyloxyphenyl)-ethyl!-3-tetrazolyl-2(1H)-pyridinone

(A) A mixture of 6- 2-(2-benzyloxyphenyl)ethyl!-3-cyano-2(1 H)pyridinone(165 mg), sodium azide (130 mg) and ammonium chloride (115 mg) in dryDMF (10 ml) was stirred and heated at 90° C. for 72 hours. The mixturewas poured into water (100 ml) and extracted with ethyl acetate (100ml). The extracts were washed with water (2×100 ml) and brine (1×100ml), dried (sodium sulphate), filtered and evaporated to dryness. Theresidue was purified by chromatography on silica gel usingdichloromethane: methanol: acetic acid (19:1:0, 95:5:1, 90:10:1) aseluant then triturated with diethyl ether, filtered and dried. There wasthus obtained 6- 2-(2-benzyloxyphenyl)-ethyl!-3-tetrazolyl-2(1H)-pyridinone (106 mg), m.p. >260° C.

The starting material was obtained as follows:

(B) A mixture of 2-benzyloxybenzaldehyde (5 g, Apin) and sodiumborohydride (1.4 g) in ethanol (50 ml) was stirred under argon for 1hour. The solvent was evaporated, the residue dissolved in ethyl acetateand added dropwise to 0.1M hydrochloric acid solution (200 ml) at 0° C.The organic solution was washed with saturated aqueous sodium hydrogencarbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filteredand evaporated to give 2-benzyloxybenzyl alcohol (4.91 g) as an oil.

C) To a solution of 2-benzyloxybenzyl alcohol (4.83 g) in diethyl ether(40 ml) was added dropwise, at 0° C., a solution of phosphorustribromide (6.27 g) in diethyl ether (10 ml). The mixture was warmed toambient temperature, diluted with diethyl ether (100 ml) and filteredthrough a pad of silica gel washing with 1 litre of diethyl ether. Thecombined organic solution was washed with saturated aqueous sodiumhydrogen carbonate (100 ml) and brine (100 ml), dried (sodium sulphate),filtered and evaporated to give 2-benzyloxybenzyl bromide (5.88 g) as anoil.

(D) 3-Cyano-6-methyl-2(1 H)-pyridinone (0.67 g, Aldrich) was added to aTHF (50 ml) solution of lithium diisopropylamide (11 mmol, prepared bythe standard method) and stirred under argon at -5° C. for 2 hours.2-Benzyloxybenzyl bromide (1.39 g) in THF (10 ml) was added and themixture stirred, at 0° C., for 1 hour. The solvent was evaporated, theresidue dissolved in water (100 ml) and washed with diethyl ether (2×100ml) and hexane (100 ml) and filtered. A precipitate was collected. Theaqueous filtrate was cooled (ice bath) and acidified (acetic acid) topH4. The resulting precipitate was filtered and combined with the othersolid, triturated with 1:1 dichloromethane:diethyl ether and dried.There was thus obtained 6- 2-(2-benzyloxyphenyl)ethyl!-3-cyano-2(1H)-pyridinone (0.94 g), m.p. 211°-213° C.

EXAMPLE 85

The process described in example 84 was repeated with the appropriate 6-2-(2-benzyloxyphenyl)ethyl!-3-cyano-2(1 H)-pyridinone to give thecompounds described in the following table with appropriatemodifications described in the notes below.

    ______________________________________                                         ##STR211##                                                                   Compd. No.                                                                              R1      R2     R3  m.p.      Footnotes                              ______________________________________                                        1         Br      H      H   >260° C.                                                                         a                                      2         Cl      H      H   220-222° C.                                                                      b,c                                    3         NO.sub.2                                                                              H      H   >260° C.                                                                         d,e                                    4         Br      Me     H   258-259° C.                                                                      f                                      5         Br      H      Br  >260° C.                                                                         g                                      6         NO.sub.2                                                                              Me     H   >260° C.                                                                         e,h                                    7         NO.sub.2                                                                              Me     Br  257-259° C.                                                                      i                                      8         Br      Me     Br  253-255° C.                                                                      j                                      ______________________________________                                        Footnotes                                                                     a:  2-benzyloxy-5-bromobenzaldehyde, used as a starting material for              the synthesis of 2-benzyloxy-5-bromobenzyl alcohol, was obtained as           follows:                                                                      A mixture of 5-bromosalicylaldehyde (12 g), potassium                         carbonate (16.5 g) and benzyl bromide (7.8 ml) in dry DMF (50 ml)             was stirred under argon for 18 hours, diluted with ethyl acetate              (200 ml) and filtered. The filtrate was washed with 0.05M HCl                 (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and            brine (100 ml), dried (sodium sulphate), filtered and evaporated to           give 2-benzyloxy-5-bromobenzaldehyde (15.8 g) m.p. 70-72° C.       b:  2-benzyloxy-5-chlorobenzaldehyde, used as a starting material for             the synthesis of 2-benzyloxy-5-chlorobenzyl alcohol, was obtained as          described in footnote a above using 5-chlorosalicylaldehyde as the            starting material.                                                        c:  6- 2-(2-benzyloxy-5-chlorophenyl)ethyl!-3-cyano-2(1H)-                        pyridinone was converted to                                                   6- 2-(2-benzyloxy-5-chlorophenyl)ethyl!-3-tetrazolyl-2(1H)-                   pyridinone using a modification of the method in Example 1 as                 follows: A mixture o 6- 2-(2-benzyloxy-5-chlorophenyl)ethyl!-3-               cyano-2(1H)-pyridinone (365 mg), sodium azide (200 mg) and                    triethylamine hydrochloride (206 mg) in dry N-methyl-                         pyrrolidinone (10 ml) was heated under argon at 150° C., for           1                                                                             hour, poured into saturated aqueous ammonium chloride (100 ml)                and extracted with ethyl acetate (100 ml). The ethyl acetate                  was evaporated and the residue purified by chromatography on                  silica gel using dichloromethane:methanol:acetic acid (95:5:1)                as eluant. The resulting solid was crystallised from DMF/water                and there was thus obtained 6- 2-(2-benzyloxy-5-chloro-                       phenyl)ethyl!-3-tetrazolyl-2(1H)-pyridinone (180 mg).                     d:  2-benzyloxy-5-nitrobenzaldehyde, used as a starting material for              the synthesis of 2-benzyloxy-5-nitrobenzyl alcohol, was obtained as           described as described in footnote a above using                              5-nitrosalicylaldehyde as the starting material.                          e:  6- 2-(2-benzyloxy-5-nitrophenyl)ethyl!-3-tetrazolyl-2(1H)-pyridinone          was obtained as described in footnote c above.                            f:  6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-1-methyl-3-tetrazolyl-2(1H)-           pyridinone was obtained from 6- 2-(2-benzyloxy-5-bromo-                       phenyl)ethyl!-3-tetrazolyl-2(1H)-pyridinone as follows:                       A mixture of 6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3-                        tetrazolyl-2(1H)-pyridinone (810 mg), sodium hydrogen carbonate               (300 mg) and chloromethyl pivalate (0.4 ml) in dry DMF (50 ml) was            stirred under argon for 14 days, poured into saturated aqueous                ammonium chloride (100 ml) and extracted with ethyl acetate                   (100 ml). The ethyl acetate solution was washed with water                    (100 ml), dried (magnesium sulphate), filtered and evaporated. The            residue was purified by chromatography on silica gel using                    dichloromethane:methanol:acetic acid (97:3:1) as eluant. A mixture            of the resulting oil (0.94 g), sodium carbonate (180 mg), and                 iodomethane (0.1 ml) in dry DMF (20 ml) was stirred under argon for           18 hours, poured into saturated aqueous ammonium chloride (100 ml)            and extracted with ethyl acetate (100 ml). The ethyl acetate was              washed with 0.05M HCl (100 ml), saturated aqueous sodium                      hydrogen carbonate (100 ml) and brine (100 ml), dried (sodium                 sulphate), filtered and evaporated to give a yellow foam (560 mg)             after purification by chromatography on silica gel using                      dichloromethane:ethyl acetate (100:, 95:5, 90:10, 80:20) as eluant.           To a solution of the foam (560 mg) in methanol (10 ml) was added a            solution of sodium hydroxide (0.1 g) in water (1.5 ml) and the                mixture stirred for 18 hours. The solvents were evaporated and the            residue triturated with acetic acid (10 ml). The resulting solid was          filtered and crystallised from DMF/water to give 6- 2-(2-benzyloxy-           5-bromophenyl)ethyl!-1-methyl-3-tetrazolyl-2(1H)-pyridinone.              g:  To a solution of compound 1 (0.75 g, see above for preparation) in            dry DMF (40 ml) was added bromine (0.1 ml) dropwise. The mixture              was stirred for 18 hours, the precipitate filtered off, washed with           DMF and dried. There was thus obtained 6- 2-(2-benzyloxy-5-                   bromophenyl)ethyl!-5-bromo-3-tetrazolyl-2(1H)-pyridinone (447 mg).        h:  2- 2-benzyloxy-5-nitrophenethyl!-5-(5-tetrazolyl)-1-methylpyridine            was obtained from                                                             2- 2-benzyloxy-5-nitrophenethyl!-5-(5-tetrazolyl)pyridine by a                similar                                                                       process to that described in footnote f.                                  i:  6- 2-benzyloxy-5-nitrophenethyl!-5-bromo-1-methyl-3-(5-tetrazolyl)-           2(1H)-pyridinone was obtained from 6- 2-benzyloxy-5-                          nitrophenethyl!-1-methyl-3-(5-tetrayolyl)-2-(1H)-pyridinone by a              similar process to that described in footnote g.                          j:  6- 2-benzyloxy-5-bromophenethyl!-5-bromo-1-methyl-3-(5-                       tetrazyolyl)-2(1H)-pyridinone was obtained from                               6- 2-benzyloxy-5-bromophenethyl!-1-methyl-3-(5-tetrazolyl)-2-(1H)-            pyridinone by a similar process to that described in footnote g.      

EXAMPLE 86 6- 2-(2-Benzyloxy-phenyl)ethyl!-3-carboxy-2(1 H)-pyridinone

(A) A solution of 6-2-(2-benzyloxyphenyl)ethyl)-3-tertbutoxy-carbonyl-2(1 H)-pyridinone (400mg) in 98% formic acid (1 ml) was left to stand for 44 hours, trituratedwith diethyl ether and the resulting solid filtered and dried. There wasthus obtained 6- 2-(2-benzyloxyphenyl)ethyl!-3-carboxy-2(1 H)-pyridinone(266 mg) m.p. 214°-215° C.

6- 2-(2-Benzyloxyphenyl)ethyl!-3-tertbutoxycarbonyl-2(1 H)-pyridinonewas obtained as follows:

(B) 3-tertbutoxycarbonyl-6-methyl-2(1 H)-pyridinone (1.49 g, J. Het.Chem., 1981, 18, 1611) was added to a THF (20 ml) solution of lithiumdiisopropylamide (14.3 mmol, prepared by the standard method) andstirred under argon, at -30° C., for 2.5 hours. 2-Benzyloxybenzylbromide (2 g, prepared as described in Example 1) in THF (10 ml) wasadded and the mixture stirred, at -30° C., for 1 hour, then warmed toambient temperature. The mixture was poured into saturated aqueousammonium chloride (200 ml) and extracted with dichloromethane. Thesolvent was evaporated and crystallised from isopropranol. There wasthus obtained 6-(2- 2-benzyloxyphenyl)ethyl!-3-tertbutoxycarbonyl-2(1H)-pyridinone (1.85 g) m.p. 146°-147° C.

EXAMPLE 87

The process described in Example 86 was repeated with the appropriate 6-2-(2-benzyloxyphenyl)ethyl!-3-tertbutoxycarbonyl-2(1 H)-pyridinones togive the compounds described in the following table with appropriatemodifications described in the notes below.

    ______________________________________                                         ##STR212##                                                                   Compound                                                                              R      Ring            mpt    Footnotes                               ______________________________________                                        1       Br                                                                                    ##STR213##     233-235                                                                              a                                       2       NO.sub.2                                                                             "               225-227                                                                              b                                       3       Br                                                                                    ##STR214##     175-176                                                                              a,c                                     4       NO.sub.2                                                                             "               195-197                                                                              b,d                                     5       CN                                                                                    ##STR215##     220-222                                                                              e                                       ______________________________________                                        a:  The preparation of 2-benzyloxy-5-bromobenzaldehyde is described in            Example 2, footnote a. It was converted to 2-benzyloxy-5-                     bromobenzyl bromide by the general method described in Example                84, (B) and (C).                                                          b:  The preparation of 2-benzyloxy-5-nitrobenzaldehyde is described in            Example 2, footnote d. It was converted to 2-benzyloxy-5-                     nitrobenzyl bromide by the general method described in Example 84,            (B) and (C).                                                              c:  6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3-tertbutoxycarbonyl-                  1-methyl-2(1H)-pyridinone was obtained from                                   6- 2-(2-benzyloxy-5-bromo-phenyl)-ethyl!-3-                                   tertbutoxycarbonyl-2(1H)pyridinone as follows:                                A mixture of 6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3-tertbutoxy-             carbonyl-2(1H)-pyridinone (2 g, prepared as described for compound            1 (Example 4) above), sodium carbonate (0.44 g) and iodomethane               (0.26 ml) in dry DMF was stirred under argon for 18 hours, poured             into water (100 ml) and extracted with ethyl acetate (2 × 100           ml).                                                                          The organic solution was washed with brine (3 × 100 ml), dried          (sodium sulphate), filtered and evaporated. The residue was purified          by chromatography on silica gel using dichloromethane:methanol                (100:0, 99:1) as eluant. The resulting solid was triturated with              pentane/diethyl ether and dried. There was thus obtained 6- 2-(2-             benzyloxy-5-bromophenyl)-ethyl!-3-tertbutoxycarbonyl-1-methyl-                2(1H)-pyridinone (1.61 g) m.p. 147.5-148.5° C.                     d:  6- 2-(2-benzyloxy-5-nitrophenyl)ethyl!-3-tertbutoxycarbonyl-                  1-methyl-2(1H)-pyridinone was obtained from 6- 2-(2-benzyloxy-5-              nitrophenyl)ethyl!-3-tertbutoxycarbonyl-2(1H)-pyridinone by the               method described in footnote c above.                                     e:  3-bromomethyl-4-benzyloxybenzonitrile was synthesised as                      follows:-                                                                     (A) 2-Hydroxy-5-formylbenzoic acid (commercially available)                   was converted to benzyl 2-benzyloxy-5-formylbenzoate by a similar             method to that of Example 1, (I) (using two equivalents of K.sub.2            CO.sub.3 and                                                                  benzyl bromide). Benzyl 2-benzyloxy-5-formylbenzoate was                      converted to benzyl 2-benzyloxy-5-hydroxyiminomethylbenzoate                  by a similar method to that of Example 3 Footnote q.                          (B) To a solution of DMAP (1.86 g) in CH.sub.2 Cl.sub.2 (50 ml) at            -10° C. was added thionyl chloride (0.98 ml) in CH.sub.2               Cl.sub.2 (10 ml).                                                             The reaction was stirred for 5 minutes, then a solution of benzyl             2-benzyloxy-5-hydroxyiminomethylbenzoate (4.4 g) in CH.sub.2 Cl.sub.2         (40                                                                           ml) was added, at -5° C. The reaction was stirred for 10               minutes at                                                                    -10° C., then a solution of DMAP (1.86 g) in CH.sub.2 Cl.sub.2         (20 ml) was                                                                   added. The reaction was stirred at 20° C. for 10 minutes,              poured into                                                                   water and the organic layer washed with 0.05N aqueous HCl,                    saturated aqueous NaHCO.sub.3 and brine, dried (MgSO.sub.4),                  filtered and evaporated to give benzyl 2-benzyloxy-5-cyanobenzoate            (4.2 g).                                                                      (C) The benzyl ester was converted to the corresponding                       methyl ester by hydrolysis (method of Example 1 (A)), acid chloride           formation and addition of methanol which was carried out using a              similar method to that of Example 1 (A), replacing the amine with             methanol.                                                                     (D) To a solution of methyl 2-benzyloxy-5-cyanobenzoate                       (17.2 g) in THF (200 ml) was added LiBH.sub.4 (3.5 g). The reaction           was                                                                           heated at reflux for 1 hour, the solvent evaporated and the residue           extracted with ethyl acetate and washed with 1N aqueous HCl,                  saturated aqueous NaHCO.sub.3 and brine, dried (MgSO.sub.4), filtered         and                                                                           evaporated. The residue was filtered through 7734 silica gel,                 eluting with 2.5% EtOAc/CH.sub.2 Cl.sub.2, to give 2-benzyloxy-5-             cyanobenzylalcohol as a white solid (12.1 g); mpt 98-100° C.           The                                                                           "benzyl alcohol" was converted to 3-bromomethyl-4-benzyloxy-                  benzonitrile by a similar method to that of Example 84 (C).           

EXAMPLE 88 2- 2-(2-Benzyloxyphenyl)ethyl!pyrimidin-6(1H)-one-5-carboxylic acid

(A) To a mixture of ethyl 2- 2-(2-benzyloxyphenyl!ethyl!- pyrimidin-6(1H)-one-5-carboxylate (3.3 g) in ethanol (100 ml) was added 2M sodiumhydroxide (10 ml). The mixture was stirred for 18 hours, the solventsevaporated and the residue acidified with 1M HCl and the precipitatefiltered off. There was thus obtained 2-2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1 H)-one-5-carboxylic acid (2.38g) mp. 192°-194° C.

Ethyl 2- 2-(2-benzyloxyphenol)ethyl!pyrimidin-6(1 H)-one-5-carboxylatewas obtained as follows:

(B) 2-(2-Hydroxyphenyl)propionic acid was benzylated with twoequivalents of benzyl bromide using the process described in Example 85,footnote a to give benzyl 2-(2-benzyloxyphenyl)propionate.

(C) Benzyl 2-(2-benzyloxyphenyl)propionate was converted to2-(2-benzyloxyphenyl)propionic acid using a similar method to thatdescribed above for the hydrolysis of ethyl 2-2-(2-benzyloxyphenyl)-ethyl!pyrimidin -6(1 H)-one-5-carboxylate.

(D) To a mixture of 2-(2-benzyloxyphenyl)propionic acid (42.81 g) indichloromethane at 0° C. was added oxalyl chloride (17.37 ml) and 1 dropof DMF. The mixture was stirred for 2 hours at ambient temperature,evaporated to dryness and the residue dissolved in THF (50 ml). Thissolution was added to aqueous ammonia (200 ml) in THF (50 ml) at 0° C.and the mixture stirred at ambient temperature for 18 hours. The mixturewas concentrated and the resulting precipitate filtered and dried. Therewas thus obtained 2-(2-benzyl-oxyphenyl)propionamide (33.74 g).

(E) To a mixture of 2-(2-benzyloxyphenyl)propionamide (33.74 g) in THF(50 ml) was added pyridine (32.03 ml). The mixture was cooled at 0° C.and trifluoroacetic anhydride was added. The mixture was stirred atambient temperature for 18 hours. The solvents were evaporated and theresidue dissolved in ethyl acetate (200 ml), and washed with water (100ml) sodium bicarbonate (100 ml) and brine (100 ml). The organic solutionwas dried (magnesium sulphate), filtered and evaporated. The residue wasdissolved in dichloromethane (200 ml) and filtered through a pad ofsilica gel and evaporated. There was thus obtained2-(2-benzyloxyphenyl)propionitrile (28 g).

(F) To a mixture of ammonium chloride (4.49 g) in toluene (25.5 ml) at5° C. was added trimethylaluminium (2M solution in toluene, 42 ml. Themixture was stirred for 2 hours. 2-(2-benzyloxyphenyl)-propionitrile (10g) in toluene (50 ml) was added and the mixture heated at 80° C. for 18hours. The cooled mixture was poured into a slurry of silica gel inchloroform, stirred for 5 minutes and filtered. The silica gel waswashed with methanol and the combined organic solutions evaporated togive 2-(2-benzyloxyphenyl)propionamidine (16 g).

(G) Sodium (0.9 g) was added to ethanol (100 ml), the solution cooled to0° C. and 2-(2-benzyloxyphenyl)propionamidine (10 g) and diethylethoxymethylene malonate (8.75 ml) added and the mixture heated underreflux for 3 hours. The solvent was evaporated and the residue acidifiedto pH4 with 1M HCl. The mixture was mixed with ethyl acetate (100 ml)and the precipitate filtered off to give ethyl 2-2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1 H)-one-5-carboxylate (3.3 g).

EXAMPLE 89

The process described in example 88 was repeated with the modificationsdescribed in the footnotes to give the following compounds:

    ______________________________________                                         ##STR216##                                                                   Compound                                                                              R     X         R   R.sup.1                                                                              mpt    Footnote                            ______________________________________                                        1       Br    CH.sub.2 CH.sub.2                                                                       H   CO.sub.2 H                                                                           192-194                                                                              a                                   2       Br    CH.sub.2 CH.sub.2                                                                       Et  CO.sub.2 H                                                                           135-136                                                                              a,b                                 3       H     (CH.sub.2).sub.3                                                                        H   CO.sub.2 H                                                                           158-160                                                                              c                                   4       H     (CH.sub.2).sub.2                                                                        H   CH.sub.2 CO.sub.2 H                                                                  190-191                                                                              d                                   ______________________________________                                        a: Methyl 2-(2-benzyloxy-5-bromophenyl)propionate was prepared as             follows:                                                                      To a solution of 2-(2-hydroxyphenyl)propionic acid (50 g) in methanol         at 0-5° C. was added dropwise thionyl chloride (22.4 ml). The          mixture was warmed to ambient temperature, stirred for 18 hours,              evaporated and the residue dissolved in ethyl acetate (200 ml) washed         with sodium bicarbonate (2 × 100 ml) and brine (100 ml), dried          (magnesium sulphate) and evaporated to give methyl 2-(2-hydroxy-              phenyl)propionate (54 g).                                                     A mixture of methyl 2-(2-hydroxyphenyl)propionate (27.15 g) and               tetrabutylammonium tribromide (80 g) in chloroform (100 ml) was               stirred for 4 hours, the solution washed with sodium thiosulphate             (2 × 100 ml) and water (2 × 200 ml). The organic solution         was dried (magnesium sulphate) and evaporated. The resulting oil was          purified by chromatography on silica gel using ethyl acetate: hexane          (3:7) as eluant to give emthyl 2-(2-hydroxy-5-bromophenyl)propionate          (22.9 g).                                                                     b:- A similar method to that of Example 88 (F) was used with                  ethylammonium chloride in the place of ammonium chloride.                     c:- 4-(2-Benzyloxyphenyl)butanenitrile was prepared as follows:-              (A) Methyl 3-(2-benzyloxyphenyl)propionate was converted to                   3-(2-benzyloxyphenyl)-1-propanol by a similar method to that of               Example 87, Footnote e (D), using diethyl ether in place of THF as            solvent.                                                                      (B) To a solution of 3-(2-benzyloxyphenyl)-1-propanol (25 g) in               CCl.sub.4 (100 ml) and CHCl.sub.3 (100 ml) was added triphenyl-               phosphine (50 g). The reaction was heated at reflux for 1 hour and            filtered through silica gel to give an oil (48 g). The oil was                dissolved in DMSO (150 ml) and sodium cyanide (10 g) added. The               mixture was heated at 120° C. for 2 hours, cooled to 20°        C.,                                                                           poured onto aqueous ferrous sulphate solution and extracted with              diethyl ether. The organic layer was washed (water), dried (MgSO.sub.4)       filtered through silica gel and evaporated to give 4-(2-benzyloxyphenyl)      butanenitrile (22.8 g) as an oil.                                             d:- Diethyl hydroxymethylene succinate was used in place of diethyl           ethoxymethylene malonate.                                                 

EXAMPLE 90 N1-Methyl-2- 2-(2-Benzyloxyphenyl)-ethyl!pyrimidin-6(1H)-one-5-carboxylic acid

(A) To a mixture of methyl N1-methyl-2-2-(2-benzyloxyphenyl)-ethyl!pyrimidin-6(1 H)-one-5-carboxylate (0.41 g)in pyridine (10 ml) was added LiI (0.3 g). The mixture was heated at100° C. for 3 hours, LiI (0.3 g) was added and the mixture heated for afurther 3 hours, and poured into 2M HCl. The resulting precipitate wasfiltered and dried. There was thus obtained N1-methyl-2-2-(2-benzyloxyphenyl)-ethyl!pyrimidin-6(1 H)-one-5-carboxylic acid (190mg) mp. 143°-144° C.

Methyl N1-methyl-2- 2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1H)-one-5-carboxylate was obtained as follows:

(B) N-Methyl-2-(2-benzyloxyphenyl)propionamidine was prepared by themethod described in Example 88 for the synthesis of2-(2-benzyloxy-phenyl) propionamidine using methylamine hydrochlorideinstead of ammonium hydrochloride.

(C) Ethyl N1-methyl-2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1H)-one-5-carboxylate was prepared fromN-methyl-2-(2-benzyloxyphenyl)-propionamidine by a similar method tothat described in Example 88 for the synthesis of ethyl 2-2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1 H)-one-5-carboxylate usingdimethyl methoxymethylene malonate instead of diethyl ethoxymethylenemalonate.

(D) A mixture of ethyl N1-methyl-2-2-(2-benzyloxyphenyl)-ethyl!pyrimidin-6(1 H)-one-5-carboxylate (0.5 g)and para-toluene sulphonic acid (30 mg) in methanol was heated underreflux for 18 hours, 150 mg of para-toluene sulphonic acid was added andthe mixture heated under reflux for a further 24 hours. The solvent wasevaporated to give methyl N1-methyl-2-2-(2-benzyloxyphenyl)ethyl!-pyrimidin-6(1 H)-one-5-carboxylate (410 mg).

EXAMPLE 91 2- (E)-2-(2-Benzyloxy-5-bromophenyl)ethenyl!-4(1H)-oxo-5-pyridinecarboxylic acid

(A) The title compound was prepared from ethyl 2-(E)-2-(2-benzyloxy-5-bromophenyl)ethenyl!-4(1H)-oxo-5-pyridinecarboxylate by a similar method to that of Example 1,(A) and purified by crystallisation from DMF/water mixtures; mpt272°-272.5° C.

The ester was prepared as follows:

(B) A mixture of 2-benzyloxy-5-bromobenzyaldehyde (18.49 g), malonicacid (13.22 g), piperidine (1.26 ml) and pyridine (200 ml) was heated at100° C. for 3 hours, poured onto ice cold 2M aqueous HCl and theresulting solid isolated by filtration. The solid was dissolved in ethylacetate, washed with 2M aqueous HCl (3 times) and brine, dried (MgSO₄),filtered and evaporated to give(E)-3-(2-benzyloxy-5-bromophenyl)prop-2-enoic acid as a whitecrystalline solid (19 g).

(C) (E)-3-(2-Benzyloxy-5-bromophenyl)prop-2-enoic was converted to(E)-3-(2-benzyloxy-5-bromophenyl)acryloyl chloride by the first part ofthe method of Example 44. The acid chloride (5.27 g) and ethyl2-dimethylaminomethylene)-3-oxobutanoate (2.31 g) were added in THF to a1M THF solution of LiN(SiMe₃)₂ (30.26 ml), at -70° C., dropwise over 2minutes. The reaction was stirred at ambient temperature for 3 mintues,then acetic acid (25.1 ml) and ammonium acetate (1.25 g) added and thesolvent evaporated. The residue was heated at 80° C. for 90 minutes,extracted with CH₂ C₂, washed with water, dried (MgSO₄), filtered andevaporated. The residue was purified by flash chromatography on silicagel, eluting with CH₂ Cl₂ :hexane (9:1) to give ethyl 2-(E)-2-(2-benzyloxy-5-bromophenyl)ethenyl!-4(1H)-oxo-5-pyridinecarboxylate (1.55 g).

EXAMPLE 92

The compounds listed in the table were prepared by a similar method tothat of Example 1 (A), from the appropriate ester derivatives.

    ______________________________________                                         ##STR217##                                                                   Compound R       Link       mpt      Footnote                                 ______________________________________                                        1        Br      CH.sub.2 CH.sub.2                                                                        217.5-219                                                                              a                                        2        NO.sub.2                                                                              (E)CHCH    202.5-203                                                                              b                                        3        NO.sub.2                                                                              (CH.sub.2).sub.2                                                                         240-240.5                                                                              c                                        4        H       (CH.sub.2).sub.2                                                                         233.5-234                                                                              d                                        ______________________________________                                        Footnotes                                                                     a:- The ester, ethyl 2- 2-benzyloxy-5-bromophenethyl!-4(1H)-oxo-5-            pyridinecarboxylate, was prepared from ethyl 2- (E)-2-(2-benzyloxy-5-         bromophenyl)ethenyl!-4(1H)-oxo-5-pyridine-carboxylate by a similar            method to that of Example 7 (E).                                              b:- The ester, ethyl 2- (E)-2-(2-benzyloxy-5-nitrophenyl)ethenyl!-4(1H)-      oxo-5-pyridine carboxylate, was prepared from 2-benzyloxy-5-nitrobenzal-      dehyde using similar processes to those described in example Example 91.      c:- The ester, ethyl 2- 2-benzyloxy-5-nitrophenethyl!-4-(1H)-oxo-5-           pyridine carboxylate, was prepared from ethyl 2- (E)-2-(2-benzyloxy-5-        nitrophenyl) ethenyl!-4(1H)-oxo-5-pyridine carboxylate by a similar           method to that of Example 7 (E).                                              d:- The ester, ethyl 2- 2-benzyloxyphenethyl!-4-(1H)-oxo-5-pyridine           carboxylate, was prepared from ethyl 2- (E)-2-(2-benzyloxyphenyl)             ethenyl!-4(1H)-oxo-5-pyridinecarboxylate by a similar method to that of       Example 1 (E). The "olefin" was prepared from 3-(2-benzyloxyphenyl)           propenoic acid by a similar method to that of Example 91(C).              

EXAMPLE 93 2- 2-Benzyloxyphenethyl!-4-methoxy-5-pyridinecarboxylic acid

(A) The title compound was prepared from methyl 2-2-benzyloxyphenethyl)-4-methoxy-5-pyridinecarboxylate by a similarmethod to that of Example (A) and purified by crystallisation from ethylacetate/hexane mixtures; mpt 181.5°-182° C.

The methyl ester was prepared as follows:

(B) Triphenylphosphine (0.27 g) and methanol (0.04 ml) were added toethyl 2- 2-benzyloxyphenethyl!-4-(1 H)-oxo-5-pyridinecarboxylate (0.35g) in toluene. After 5 minutes, diethyl azodicarboxylate (0.24 g) wasadded and the reaction mixture stirred for 18 hours. The mixture wasdiluted with ethyl acetate and washed with water and brine, dried(MgSO₄), filtered and evaporated. The residue was purified by MPLC onsilica gel, eluting with ethyl acetate:hexane (2:8), to give methyl 2-2-benzyloxyphenethyl)-4-methoxy-5-pyridinecarboxylate as a white solid(0.25 g).

EXAMPLE 94 3- 6-(2-Benzyloxy-5-cyanophenethyl)-2-(1H)-oxo-3-pyridyl!ureidoacetic acid

The title compound was prepared from methyl 3-6-(2-benzyloxy-5-cyanophenethyl)-2-(1 H)-oxo-3-pyridyl!ureidoacetate bya similar method to that of Example 1 (A).

The ester was prepared from 6- 2-benzyloxy-5-cyanophenethyl!-2(1H)-oxo-3-pyridinecarboxylic acid and glycine methyl ester by a similarmethod to that of example 56 (A).

EXAMPLE 95

(A) A mixture of 6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3carboxy-2(1H)pyridinone (1.0 g) and 1,1'-carbonyldiimidazole (0.76 g) in dry THF(40 ml) was heated at 50° C. for 3 hours under argon. The solvent wasevaporated and the residue mixed with ethanolamine (0.6 ml) anddichloromethane (50 ml) and stirred for 18 hours. The mixture waspurified by subjecting to chromatography on silica gel usingdichloromethane:methanol (95:5) as eluant. The resulting residue wascrystallised from isopropanol. There was thus obtained 6-2-(2-benzyloxy-5-bromophenyl)ethyl!-3-(2-hydroxyethylcarbamoyl)-2(1H)pyridinone (0.77 g), m.p. 164°-166° C.

6- 2-(2-Benzyloxy-5-bromophenyl)ethyl!-3-carboxy-2(1 H)-pyridinone wasprepared as follows:

(B) A mixture of 5-bromosalicylaldehyde (12 g), potassium carbonate(16.5 g) and benzyl bromide (7.8 ml) in DMF (50 ml) was stirred for 18hours, poured into ethyl acetate (100 ml), washed with 0.05M HCl (100ml), sodium bicarbonate (100 ml) and brine (100 ml), dried (sodiumsulphate), filtered and evaporated. The residue was triturated withhexane/diethyl ether to give 2-benzyloxy-5-bromo-benzaldehyde (15.8 g)mp.70°-72° C.

(C) A mixture of 2-benzyloxy-5-bromobenzaldehyde (14.55 g) and sodiumborohydride (2.6 g) in ethanol (250 ml) was stirred under argon for 1hour. The solvent was evaporated, the residue dissolved in ethyl acetateand added dropwise to 0.1M hydrochloric acid solution (200 ml) at 0° C.The organic solution was washed with saturated aqueous sodium hydrogencarbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filteredand evaporated to give 2-benzyloxy-5-bromobenzyl alcohol (14.85 g) as anoil. To a solution of 2-benzyloxy-5-bromobenzyl alcohol (14.75 g) indiethyl ether (150 ml) was added dropwise, at 0° C., to a solution ofphosphorus tribromide (13.68 g) in diethyl ether (40 ml). The mixturewas warmed to ambient temperature, diluted with diethyl ether (200 ml)and filtered through a pad of silica gel (200 g) washing with 1 litre ofdiethyl ether. The combined organic solution was washed with saturatedaqueous sodium hydrogen carbonate (150 ml) and brine (150 ml), dried(sodium sulphate), filtered and evaporated to give2-benzyloxy-5-bromobenzyl bromide (15.2 g).

(D) 3-Tertbutoxycarbonyl-6-methyl-2(1 H)-pyridinone (2.94 g) J. Het.Chem., 1981, 18, 1611! was added to a THF (50 ml) solution of lithiumdiisopropylamide (32 mmol) prepared by the standard method! and stirredunder argon at -30° C. for 2.5 hours. 5-Bromo-2-benzyloxy-benzylbromide(5 g) in THF (40 ml) was added and the mixture stirred at -30° C. for 1hour then warmed to ambient temperature. The mixture was poured intosaturated aqueous ammonium chloride (200 ml) and extracted with ethylacetate (2×100 ml). The combined organic solutions were washed withbrine (100 ml), dried (sodium sulphate) and evaporated. The residue wastriturated with dichloromethane. There was thus obtained 6-2-(2-benzyloxy-5-bromophenyl)ethyl)-3-tertbutoxycarbonyl-2(1H)-pyridinone (5 g) mp. 190°-192° C.

(E) A solution of 6-2-(2-benzyloxy-5-bromophenyl)ethyl!-3-tertbutoxycarbonyl-2(1H)-pyridinone (3.23 g) in 98% formic acid (6 ml) was left to stand for18 hours, triturated with diethyl ether and the resulting solid filteredand dried. There was thus obtained 6-2-(2-benzyloxy-5-bromophenyl)ethyl!-3-carboxy-2(1 H)-pyridinone (2.68 g)m.p. 233°-235° C.

EXAMPLE 96

A similar method to that described in Example 95 (A) was used to preparethe compounds listed in the table from the appropriate carboxylic acidand amine derivatives.

    __________________________________________________________________________     ##STR218##                                                                   Compound                                                                            R.sup.1                                                                          n     Ar      R.sup.2    mpt   Footnote                              __________________________________________________________________________    1     Br 2                                                                                    ##STR219##                                                                           CH.sub.2 CH.sub.2 CH.sub.3                                                               123-125                                     2     Br 2     "                                                                                      ##STR220##                                                                              153-155                                     3     Br 2     "                                                                                      ##STR221##                                                                              165-166                                     4     NO.sub.2                                                                         2     "       CH.sub.2 CH.sub.2 OH                                                                     199-201                                                                             a                                     5     Br 2                                                                                    ##STR222##                                                                           "          187-188                                                                             b                                     6     NO.sub.2                                                                         2     "       "          228-229                                                                             a, c                                  7     H  2                                                                                    ##STR223##                                                                           CH.sub.2 CH.sub.2 CH.sub.3                                                               155-156                                                                             d                                     8     H  2     "                                                                                      ##STR224##                                                                              147-148                                                                             d                                     9     H  2     "       CH.sub.2 CH.sub.2 OH                                                                     170-171                                                                             d                                     10    NO.sub.2                                                                         2     "       CH.sub.2 CH.sub.2 CH.sub.3                                                               151-153                                                                             a                                     11    NO.sub.2                                                                         2     "                                                                                      ##STR225##                                                                              155-160                                                                             a                                     12    H  3                                                                                    ##STR226##                                                                            ##STR227##                                                                              93-94                                       13    Br 2                                                                                    ##STR228##                                                                           (CH.sub.2).sub.4 OH                                                                      164-165                                     14    Br 2     "                                                                                      ##STR229##                                                                              157-158                                     15    Br 2     "                                                                                      ##STR230##                                                                              194.5-195.5                                 16    Br 2     "                                                                                      ##STR231##                                                                              250-251.5                                   17    Br 2     "                                                                                      ##STR232##                                                                              203-203.5                                   18    Br 2     "                                                                                      ##STR233##                                                                              265-267.5                                   19    Br 2     "       CH.sub.2 CH(OH)CH.sub.3                                                                  163.5-164                                   20    Br 2                                                                                    ##STR234##                                                                           (CH.sub.2).sub.3 OH                                                                      121.5-122.5                                 21    Br 2     "       CH.sub.2 CH(OH)CH.sub.2 OH                                                               162.5-163.5                                 22    H  2                                                                                    ##STR235##                                                                           H          116-117                                     23    H  3     "       H          114-114.5                                   24    H  2                                                                                    ##STR236##                                                                           H          137.5-138                                   25    H  3     "       H          124.5-125.5                                 26    Cl 2     "       H          125.5-128.5                                 27    Br (E)CHCH                                                                              ##STR237##                                                                           CH.sub.2 CH.sub.2 OH                                                                     254-255                                     28    Br (E)CHCH                                                                             "                                                                                      ##STR238##                                                                              243.5-244                                   29    Br (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 CH.sub.3                                                               217.5-218                                   30    Br (CH.sub.2).sub.2                                                                    "       CH.sub.2 CH.sub.2 OH                                                                     207.5-208                                   31    Br (CH.sub.2).sub.2                                                                    "       CH.sub.2 CH.sub.2 CH.sub.3                                                               172-172.5                                   32    Br (CH.sub.2).sub.2                                                                    "                                                                                      ##STR239##                                                                              195.5-196                                   33    Br (CH.sub.2).sub.2                                                                    "       H          222.5-223.5                                 34    H  (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 OH                                                                     216-218                                     35    H  (E)CHCH                                                                             "       CH.sub.2 CH.sub.2 CH.sub.3                                                               199.5-200.5                                 36    H  (E)CHCH                                                                             "                                                                                      ##STR240##                                                                              187.5-188.5                                 37    H  (CH.sub.2).sub.2                                                                    "       "          149.5-150.5                                 38    H  (CH.sub.2).sub.2                                                                    "       CH.sub.2 CH.sub.2 CH.sub.3                                                               132-132.5                                   39    CN (CH.sub.2).sub.2                                                                     ##STR241##                                                                           "          157-159                                     40    CN (CH.sub.2).sub.2                                                                    "       CH.sub.2 CH.sub.2 OH                                                                     198-200                                     41    CN (CH.sub.2).sub.2                                                                    "                                                                                      ##STR242##                                                                              198-199                                     42    CN (CH.sub.2).sub.2                                                                    "                                                                                      ##STR243##                                                                              196-198                                     43    Br (CH.sub.2).sub.2                                                                    "                                                                                      ##STR244##                                                                              >250                                        __________________________________________________________________________    a: -5-Nitro-2-benzyloxybenzaldehyde was prepared from 5-nitro-2-hydroxyben    zaldehyde by the method                                                       described in Example 1 for the synthesis of 2-benzyloxy-5-bromobenzaldehyd    e.                                                                            b: -1-Methyl-6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3-tertbutoxycarbonyl-2    (1H)-pyridinone was                                                           synthesised from 6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3-tertbutoxycarbon    yl-2(1H)-pyridinone                                                           as follows:                                                                   A mixture of 6- 2-(2-benzyloxy-5-bromophenyl)ethyl!-3-tertbutoxycarbonyl-2    (1H)-pyridinone (2 g),                                                        sodium carbonate (0.44 g) and methyl iodide (0.26 ml) in DMF (40 ml) was      stirred for 18 hours,                                                         poured into water (100 ml) and extracted with ethyl acetate (2 ×        100 ml). The combined organic                                                 solutions were washed with brine (100 ml), dried (sodium sulphate),           filtered and evaporated. The residue                                          was purified by subjecting to chromatography on silica gel using              dichloromethane: methanol (0:100 to                                           1.5:98.5 gradient) as eluant. There was thus obtained 1-methyl-6- 2-(2-ben    zyloxy-5-bromophenyl)-                                                        ethyl!-3-tertbutoxycarbonyl-2 (1H)-pyridinone (1.61 g) mp.                    147.5-148.5° C.                                                        c: -1-Methyl-6- 2-(2-benzyloxy-5-nitrophenyl)ethyl!-3-tertbutoxy-carbonyl-    2(1H)-pyridinone was                                                          obtained from 6- 2-(2-benzyloxy-5-nitrophenyl)ethyl!- 3-tertbutoxycarbonyl    -2(1H)-pyridinone using                                                       a similar method to that described in note b for the conversion of            6- 2-(2-benzyloxy-5-bromo-phenyl)                                             ethyl!-3-tertbutoxycarbonyl-2(1H)-pyridinone to 1-methyl-6- 2-(2-benzyloxy    -5-bromophenyl)ethyl!-                                                        3-tertbutoxycarbonyl-2(1H)-pyridinone.                                        d: -2-Benzyloxybenzaldehyde was obtained commercially from Apin.          

EXAMPLE 97 2- 2-(2-Benyloxyphenyl)ethyl!-5- (3-pyridyl)methylcarbamoyl!pyrimidin-6(1 H)-one

(A) Using the method described in Example 95 for the conversion of 6-2-(2-benzyloxyphenyl-5-bromo)ethyl!-3-carboxy-2(1 H)-pyridinone to 6-2-(2-benzyloxyphenyl-5-bromo)ethyl!-3-(2-hydroxyethylcarbamoyl)-2(1H)pyridinone, 2- 2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1H)-one-5-carboxylic acid was converted to 2-2-(2-benzyloxyphenyl)ethyl!-5- (3-pyridyl)methylcarbamoyl!pyrimidin-6(1H)-one m.p. 174°-176° C.

2- 2-(2-Benzyloxyphenyl)ethyl!pyrimidin-6(1 H)-one-5-carboxylic acid wasobtained as descrbied in Example 89.

EXAMPLE 98

The process described in Example 97 was repeated with the appropriatesubstituted 2- 2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1H)-one-5-carboxylic acid or N1-methyl-2-2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1 H)-one-5-carboxylic acid andthe appropriate amine to give the compounds described in the followingtable.

    ______________________________________                                         ##STR245##                                                                   Compd. No                                                                             R1     R2    R3         m.p.   Footnote                               ______________________________________                                        1       H      H     H          198-199                                       2       H      H     n-propyl   132-135                                       3       Br     H     2-Hydroxyethyl                                                                           205-207                                                                              a                                      4       Br     H     2-Pyridylmethy1                                                                          178-179                                                                              a                                      5       Br     H     n-Propyl   173-175                                                                              a                                      6       Br     H     2-Cyanoethyl                                                                             189-200                                                                              a                                      7       H      Me    2-Pyridylmethyl                                                                          102-104                                                                              b                                      8       H      Me    n-Propyl   95-96  b                                      9       H      H     2-Pyridylmethyl                                                                          174-176                                       ______________________________________                                         a: Methyl 2(2-benzyloxy-5-bromophenyl)propionate (used in the place of        benzyl 2(2-benzyloxyphenyl)propionate) was synthesised as follows:            To a solution of 2(2-hydroxyphenyl)propionic acid (50 g) in methanol at       0-5° C. was added dropwise thionyl chloride (22.4 ml).                 The mixture was warmed to ambient temperature, stirred for 18 hours,          evaporated and the residue dissolved in ethyl acetate (200 ml) washed wit     sodium bicarbonate (2 × 100 ml) and brine (100 ml), dried (magnesiu     sulphate) and evaporated to give methyl 2(2-hydroxyphenyl)propionate (54      g).                                                                           A mixture of methyl 2(2-hydroxyphenyl)propionate (27.15 g) and                tetrabutylammonium tribromide (80 g) in chloroform (100 ml) was stirred       for 4 hours, the solution washed with sodium thiosulphate (2 × 100      ml) and water (2 × 200 ml). The organic solution was dried              (magnesium sulphate) and evaporated. The resulting oil was purified by        chromatography on silica gel using ethyl acetate:hexane (3:7) as eluant t     give methyl 2(2-hydroxy-5-bromophenyl)propionate (22.9 g).                    b: 1-Methyl-2- 2-(2-benzyloxyphenyl)ethyl!pyrimidin-6(1H)-one-5-carboxyli     acid was prepared as described in Example 88.                            

EXAMPLE 99 6-2-Benzyloxy-5-bromophenethyl!-2-chloro-3-(N-(5-tetrazolyl)carbamoyl)pyridine

The title compound was prepared as follows:

A mixture of 6- 2-benzyloxy-5-bromophenethyl!-2-(1H)-oxo-3-pyridinecarboxylic acid (1.1 g), thionyl chloride (10 ml) andDMF (0.1 ml) was heated at reflux for 1 hour, the thionyl chlorideevaporated (as an azeotrope with toluene) and the residue dissolved inCH₂ Cl₂. To this solution was added a mixture of triethylamine (3.25 ml)and 5-aminotetrazole (0.4 g) in CH₂ Cl₂ at 5° C. The reaction mixturewas stirred for 1 hour at 20° C., and washed with water twice. A whiteprecipitate formed and was isolated by filtration and dried. There wasthus obtained the title compound (0.57 g), mpt. 218°-220° C.

EXAMPLE 100

The process described in example 99, was repeated with 6- 2-benzyloxy-5-bromophenethyl!-2-(1 H)-oxo-3-pyridinecarboxylic aicd and theappropriate amine to give the compounds listed below. In each case theproduct was purified by chromtagraphy on silica gel.

    ______________________________________                                         ##STR246##                                                                   Compound     R             mpt                                                ______________________________________                                        1            CH.sub.2 CH.sub.2 OH                                                                        106-108                                            2            CH.sub.2 CH.sub.2 CH.sub.3                                                                  129-131                                                          ##STR247##   122-124                                            4                                                                                           ##STR248##   106-108                                            ______________________________________                                    

EXAMPLE 101 6-2-Benzyloxy-5-bromophenethyl!-2-methoxy-3-pyridinecarboxylic acid

Methyl 6-(2-benzyloxy-5-bromophenethyl!-2-methoxy-3-pyridinecarboxylatewas converted to the title compound (mpt 141°-143° C.) by a similarmethod to that of example 1 (A) which was modified by heating thereaction mixture at reflux for 3 hours and using MeOH as the solvent.

The methyl ester was produced as follows:

6-(2-benzyloxy-5-bromophenethyl!-2-(1 H)-oxo-3-pyridinecarboxylic acidwas converted to methyl 6-2-benzyloxy-5-bromophenethyl!-2-methoxy-3-pyridinecarboxylate by asimilar method to that of Example 99 using methanol in the place of5-aminotetrazole.

A mixture of methyl 6-2-benzyloxy-5-bromophenethyl!-2-chloro-3-pyridinecarboxylate (7.0 g) andsodium methoxide (2.5 mole equivalents) in methanol was heated at 140°C. for 5 hours in a Carius Tube. The solvent was evaporated and theresidue extracted with ethyl acetate and washed with saturated aqueousNH₄ Cl, water and brine. The organic solution was dried (Na₂ SO₄),filtered and evaporated. The residue was purified by chromatography on7734 silica gel, eluting with 1% MeOH/CH₂ Cl₂, to give methyl 6-2-benzyloxy-5-bromophenethyl!-2-methoxy-3-pyridinecarboxylate (6.16 g).

EXAMPLE 102 6- 2-Benzyloxy-5-bromophenethyl!-2-chloro-3-pyridinecarboxamide

A solution of methyl 6-2-benzyloxy-5-bromophenethyl!-2-chloro-3-pyridinecarboxylate (2.0 g) inethanol (60 ml) saturated with ammonia was heated at 177° C. underpressure for 6 hours. The solvent was evaporated and the residuesubjected to chromatography on silica gel (7734). Two products wereisolated. The first was eluted with 2.5% ethyl acetate/CH₂ Cl₂ and thesecond with 5% MeOH/CH₂ Cl₂. The first product was identified as amixture of the methyl and ethyl esters of 6-2-benzyloxy-5-bromophenethyl!-2-amino-3-pyridinecarboxylic aicd (0.3 g).The second produce was identified as the title compound (0.6 g) mpt.142°-144° C.

EXAMPLE 103 4- 3-(2-(3-Pyridylmethyloxy)phenyl)propyl!benzoic acid

Methyl 4- 3-(2-(3-pyridylmethyloxy)phenyl)propyl!benzoate (1.03 g, 2.85ml) was disolved in 1:1 MeOH/THF (20 ml total). The solution was treatedwith NaOH solution (2M, 3.4 ml, 6.8 mmol) and the reaction was allowedto stirred at ambient temperature for 18 hours. The pH was adjusted topH7 with 1N HCl and the reaction was partially evaporated andpartitioned between EtOAc/water. The aqueous layer was extracted with1-propanol/CH₂ Cl₂ (1:4). The organic extracts were combined and theresidue was dried by evaporating off toluene at reduced pressure. EA C₂₂H₂₁ NO₃. 0.33H₂ O:calc 74.8% C 6.14% H 4.0% N found 74.8% C 6.0% H 3.7%N MS FAB(-ve):346 M-H!-.

The following compounds were prepared using a similar method to thatdescribed above from the appropriate ester.

    ______________________________________                                         ##STR249##                                                                   R           MS             Footnotes                                          ______________________________________                                        2-thienyl   FAB(-ve):351 M - H!-                                                                         a,b                                                4-pyridyl   FAB(-ve):346 M - H!-                                                                         c,d                                                2-furanyl   FAB(+ve):337 M + H!+                                                                         e,f                                                ______________________________________                                         Footnotes                                                                     a: Elemental analysis: Calc for C.sub.21 H.sub.20 SO.sub.3 71.6% C, 5.72%     H, found 71.2% C, 5.6% H.                                                     b: pH adjusted to pH5.                                                        c: Elemental analysis: Calc for C.sub.22 H.sub.21 NO.sub.3.0.1H.sub.2 O       75.7% C, 6.12% H, 4.01% N; found 75.6% C, 6.2% H, 3.8% N.                     d: pH adjusted to pH6; product recrystallised from methanol/water.            e: Elemental analysis: Calc for C.sub.21 H.sub.20 O.sub.4.0.25H.sub.2 O       74.0% C, 5.94% H; found 74.0%, 6.1% H.                                        f: pH adjusted to pH5; product m.p. 68-73° C.                     

The starting materials were prepared as follows:

Methyl 4- 3-(2-hydroxyphenyl)propyl!benzoate (1.35 g, 5 mmol) wasdissolved in 0.2 ml of THF. The solution was treated with3-hydroxymethylpyridine (0.6 g, 5.5 mmol) and triphenylphosphine (1.44g, 5.5 mmol). To this mixture was added slowly diethylazodicarboxylate(0.96 g, 5.5 mmol). The reaction mixture was stired for 72 hours and thesolvent was evaporated. The amide residue was purified by chromatography(methanol, dichloromethane) to give methyl 4-3-(2-(3-pyridylmethyloxy)phenyl)propyl!benzoate as a pink oil (1.03 g,57%) MS (CI+):362 M+H!+.

The following compounds were prepared using a similar method to thatdescribed above from methyl 4- 3-(2-hydroxyphenyl) propyl!benzoate andthe appropriate alcohol.

    ______________________________________                                         ##STR250##                                                                   R             MS          Footnotes                                           ______________________________________                                        1-thienyl     CI+:366 M!+ a                                                   4-pyridyl     CI+:362 M + H!+                                                                           b                                                   2-furanyl     CI+:350 M!+ c                                                   ______________________________________                                         Footnotes                                                                     a: A total of 22 equivalents of DEAD was used. Reaction time 96 hours.        Residue was purified by chromatography eluting with diethyl ether/hexane.     b: Residue was purified by chromatography eluting with                        methanol/dichloromethane.                                                     c: Residue was purified by chromatography eluting with diethyl                ether/hexane.                                                            

EXAMPLE 104 4- 3-(4-(Benzyloxy)pyrimid-5-yl)propyl!benzoic acid

tert-Butyl 4- 3-(4-(benzyloxy)pyrimid-5-yl)propyl!benzoate (0.36 g, 0.92mmol) was dissolved in dichloromethane (0.7 ml) and treated withtrifluoro-acetic acid (1.05 g, 9.2 mmol). The reaction was stirred atamibent temperature for 2 hours. The mixture was partitioned betweenEtOAc/water and the aqueous layer extracted with EtOAc. The organiclayers were combined, dried (MgSO₄) and evaporated and the solid wastriturated with hexane and recrystallised from isopropanol/water. Thecream coloured solid was taken up in THF, filtered through Celite andevaporated to give the title product.

EA:C₂₀ H₁₈ N₂ O₃.1/8 THF

Calc 71.7% C 5.5% H 8.16% N

Found 71.6% C 5.6% H 7.9% N

MS (CI+):335 M+H!+

The starting material was prepared as follows:

5-Iodo-4-(3 H)-pyrimidinone (1.11 g, 5 mmol) and tert-butyl 4-ethynylbenzoate (1.11 g, 5.5 mmol) were dissolved in DMF (sieve dried, 2.8 ml)and treated with CuI (0.015 g, 0.0 mmol) and triethylamine (1.515 g, 15mmol). The solution was de-gassed by bubbling argon through for 5minutes. Palladium catayst (0.019 g, 0.027 mmol) was added and thereaction mixture placed in a oil bath pre-heated to 55° C. After 40minutes the reaction mixture was removed from the heat and partitionedbetween ethyl acetate and water. The aqueous layer was acidified andextracted with ethyl acetate. The organic layers were combined, driedover MgSO₄ and evaporated to give a crude product which was purified bychromatography (MeOH, CH₂ Cl₂) to give tert-butyl 4- 2-(pyrimidin-4(3H)-one-5-yl)ethynyl!benzoate (0.602 g, 41%).

MS (17/4):CI+:297 (M+H)+

Tert-butyl 4- 2-(pyrimidin-4(3 H)-one-5-yl)ethynyl!benzoate (0.59 g, 2.0mmol) was dissolved in EtOAc (20 ml) and treated withpalladium-on-carbon (0.30 g, 10%!. The reaction was placed under ahydrogen atmosphere and stirred overnight at ambient temperature. Thereaction was filtered and evaporated to give tert-butyl 4-2-(pyrimidin-4(3 H)-on-5-yl)ethyl!benzoate which was used withoutfurther purification (0.6 g, quantitative).

MS: CI+:301 M+H!+

tert-Butyl 4- 2-(pyrimidin-4(3 H)-on-5-yl)ethyl!benzoate (0.6 g,) wasdissolved in N,N-dimethylaniline (5 ml) and treated withphosphorous-oxy-chloride (1.53 g 10 mmol). The reaction was heated to100° C. for 2.5 hours and then evaporated at reduced pressure. Theresidue was diluted with EtOAc, washed (1N HCl 2×, H₂ O, saturatedbrine), dried over MgSO₄ and evaporated to give tert-butyl 4-2-(4-chloropyrimidin-5-yl)ethyl!benzoate as a brown oil (0.5 g, 64%)which was used without further purification.

MS CI:319 (M+H)-

Anhydrous benzyl alcohol (0.18 g, 1.74 mmol) was dissolved in THF (3ml). Potassium tert-butoxide was added (0.213 g, 1.9 mmol) and themixture was stirred for 5 minutes. tert-Butyl 4-2-(4-chloropyrimidin-5-yl)ethyl!benzoate (0.49 g, 1.5 mmol) was added asa solution in THF (4 ml). The reaction was stirred at ambienttemperature overnight and then partitioned between EtOAc/Water. Theaqueous layer was extracted with EtOAc and the organic layers werecombined, dried (MgSO₄) and evaporated to give an orange-yellow oil.Chromatography eluting wiht EtOAc hexane gave tert-butyl 4-3-(4-(benzyloxy)pyrimid-5-yl)propyl!benzoic acid as a yellow oil (0.41g, 70%).

MS CI+:391 M+H!+

EXAMPLE 105 4- 2-(2-Benzyloxypyrid-3-yl)ethyl!benzoic acid

Methyl 4- 2-(2-benzyloxypyrid-3-yl)ethyl!benzoate was dissolved in EtOH(5 ml) and treated with NaOH (1N, 1.04 ml). The reaction was stirred atambient temperature for 48 hours, 1N HCL (1.04 ml) was added and theprecipitate was filtered and recrystllised from iso-propanol to give 4-2-(2-benzyloxypyrid-3-yl)ethyl!benzoic acid as a white solid (0.054 g,38%).

MS (CI)+:334 M+H!+

The starting material was prepared as follows:

Sodium hydride (60%, 2.89 g, 72.3 mmol) was washed with hexane (1×) andsuspended in THF (50 ml). Anhydrous benzyl alcohol (8.57 g, 79.3 mmol)was added dropwise and the reaction mixture was stirred for 30 minutes.A solution of 2-chloronicotinonitrile (10.0 g, 72.2 mmol) in THF (50 ml)was added via a syringe (exotherm). The reaction was stirred at ambienttemperature for 18 hours then water was added to quench the reaction.The reaction mixture was partitioned between EtOAc/water and the organicphase dried (MgSO₄) and evaporated. The residue was purified bychromatography (SiO₂, CH₂ Cl₂) to give 2-benzyloxy-3-cyanopyridine as apale yellow oil which crystallised on standing (11.4 g, 75%).

MS (CI+):211 M+H!+

2-Benzyloxy-3-cyanopyridine (7.6 g, 36.2 mmol) was dissolved indichloromethane (100 ml) and a solution of DIBAL (1M in CH₂ Cl₂, 47 ml)was added dropwise over 40 minutes. The temperature of the reaction roseto 30° C. The reaction was stirred at ambient temperature (shielded fromlight) overnight. The reaction was quenched by pouring into a solutionof silica on CH₂ Cl₂. The solvent was evaporated and the silica wasapplied to the top of a column and eluted with CH₂ Cl₂. Evaporation ofthe solvent from the appropriate fractions gave2-benzyloxy-3-pyridinecarbaldehyde (7.3 g, 95%).

MS (CI+):214 M+H!+

(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (16.6 g, 33.8mmol) was suspended in THF (70 ml) under Argon. Lithiumbis(trimethylsilyl)amide (1M in THF, 40.5 ml) was added. The reactionmixture was stirred for 1 hour at ambient temperature; the colourchanged to orange. 2-Benzyloxy-3-pyridinecarbaldehyde (7.2 g, 33.8 mmol)was added as a solution in THF (50 ml) and the reaction mixture wasstirred at amibent temperature overnight (shielded from light). Thereaction mixture was partitioned between EtOAc/water, the organic phasewas dried (MgSO₄) and evaporated. Purification by chromatography (SiO₂,eluting with CH₂ Cl₂ /hexane) gave methyl 4-2-(2-benzyloxy-3-pyridyl)ethenyl!benzoate (9.2 g, 79%).

MS (CI+):346 M+H!+.

A suspension of rhodium on alumina (5%, 0.1 g) in ethanol (20 ml) wasflushed well with argon. A solution of the methyl 4-2-(2-benzyloxypyrid-3-yl)ethenyl!benzoate (1.0 g, 2.9 mmol) in ethanol(60 ml) was added. The reaction was transferred to a manometer under anatmosphere of hydrogen and the reaction was stirred at ambienttemperature until 1.4 equivalents hydrogen had been taken up. Thereaction mixture was filtered and evaporated and the residue subjectedto chromatography on SiO₂ (CH₂ Cl₂ /hexane) to give 4-2-(2-benzyloxypyrid-3-yl)ethyl!benzoic acid (0.5 g, 49%).

MS (CI+):378 M+H!+

EXAMPLE 106 4- 2-(3-Benzyloxy-2-pyridyl)ethyl!benzoic acid

A solution of methyl 4- 2-(3-benzyloxy-2-pyridyl)ethyl!benzoate (0.1 g,0.3 mmol) in EtOH (1 ml) was treated with aqueous NaOH solution (0.6 ml1N). The reaction was stirred at ambient temperature for 18 hours andthen treated with HCl soltuion (0.6 ml, 1N). The resulting precipitatewas filtered and recrystallised from isopropanol to give the titleproduct.

MS (CI+):334 M+H!+

EA:C₂₁ H₁₉ NO₃.0.25 iPrOH

Calc 75.0% C, 6.03% H, 4.02% N

Found 74.8% C, 5.7% H, 4.2% N

The starting material was prepared as follows:

To a suspension of 3-hydroxy-2-hydroxymethylpyridine hydrochloride (7.0g, 12.4 mmol) in ethanol (37.5 ml) was added a solution of KOH pellets(85% 1.6 g, 24.7 mmol) in ethanol (25 ml). The reaction was stirred for5 minutes at ambient temperature and then benzyl bromide was added (2.11g, 12.36 mmol). The reaction mixture was stirred at ambient temperaturefor 48 hours, filtered and evaporated. The residue was purified bychromatography (EtOAc, CH₂ Cl₂) to give3-benzyloxy-2-hydroxymethylpyridine as a colourless solid (1.55 g, 58%)J. Med. Chem., 15, (1972) 615! m.p. 78.7°-79.2° C.

MS (CI+):216 M+H!+

A solution of 3-benzyloxy-2-hydroxymethylpyridine (0.25 g, 1.16 mmol) inchloroform (15 ml) was treated with manganese dioxide (0.45 g, 6.34mmol). The reaction mixture was heated to reflux and held at reflux for18 hours. The reaction mixture was then filtered through Celite andevaporated to give a yellow gum. This gum was purified by chromatography(EtOAc/CH₂ Cl₂) to give 3-benzyloxy-2-pyridinecarbaldehyde as acolourless gum (0.15 g, 62%).

MS (CI+):214 M+H!+

(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (4.42 g, 9.00mmol) was suspended in THF (50 ml) under argon. Lithiumbis-(trimethylsilyl)amide (1M in THF, 10.8 ml) was added and the deeporange reaction was stirred at ambient temperature for 1 hour. Asolution of 3-benzyloxy-2-pyridinecarbaldehyde (2.0 g, 9.4 mmol) in THF(20 ml) was added and the reaction was stirred at ambient temperaturefor 2 hours 30 minutes. The reaction was partitioned betweenEtOAc/water, the aqueous phase was extracted with EtOAc, the organiclayers were combined, dried (MgSO₄) and evaporated. The residue waspurified by chromatography (EtOAc/CH₂ Cl₂) to give methyl 4-2-(3-benzyloxy-2-pyridyl)ethenyl!benzoate as a yellow oil. (3.01 g) .

MS (CI)+:346 M+H!+

Methyl 4- 2-(3-benzyloxy-2-pyridyl)ethenyl!benzoate (2.0 g, 5.8 nnol)was partially dissolved in EtOAc (20 ml) and EtOH (10 ml). The reactionvessel was flushed with argon, palladium-on-carbon (0.2 g, 10%) wasadded and the reaction was flushed with argon followed by hydrogen. Thereaction was stirred at ambient temperature for 18 hours, filtered andevaporated to give methyl 4- 2-(3-hydroxy-2-pyridyl)ethyl!benzoate as apale orange solid (1.3 g, 90%) which was used without furtherpurification.

MS (CI)+:258 M+H!+

A solution of methyl 4- 2-(3-hydroxy-2-pyridyl)ethyl!benzoate (1.1 g,4.3 mmol) in DMF (30 ml) was treated with benzyl bromide (0.89 g, 5.2mmol) and potassium carbonate (0.72 g, 5.2 mmol). The reaction wasstirred at ambient temperature overnight and then, partitioned betweenEtOAc/water. The organic phase was washed well with water, dried (MgSO₄)and evaporated. The residue was purified by chromatography (SiO₂)eluting with CH₂ Cl₂ /EtOAc to give methyl 4-2-(3-benzyloxy-2-pyridyl)ethyl!benzoate (0.94 g, 53%) as a low meltingyellow solid.

MS (CI+):348 M+H!+

EXAMPLE 107 N-(2-Hydroxyethyl)-4-2-(3-benzyloxy-2-pyridyl)ethyl!benzamide

Methyl 4- 2-(3-benzyloxy-2-pyridyl)ethyl!benzoate (0.20 g, 0.576 mmol)was dissolved in ethanolamine (3 ml) and heated to 160° C. under argonfor 2 hours. Water was added (3 ml) and the aqueous layers wereextracted with ethyl acetate and the organic phase was dried (MgSO₄) andevaporated. The residue was recrystallised from EtOAc/hexane and washedwith ether to give the title product (0.064 g, 29%).

MS (CI+):377 M+H!+

EA:C₂₂ H₂₄ N₂ O₃.1/3 H₂ O

Calc 72.25% C 6.45% H 7.33% N

Found 72.1% C 6.4% H 7.3% N

EXAMPLE 108 N-(2-Hydroxyethyl)-4-2-(2-benzyloxy-3-pyridyl)ethyl!benzamide

The title compound was prepared using a similar method to that ofExample 107 from the corresponding methyl ester.

MS CI+:377 M+H!+

EA:C₂₂ H₂₄ N₂ O₃ 1/7 H₂ O

Calc 72.9% C, 6.41% H, 7.39% N

Found 72.9% C, 6.3% H, 7.3% N

EXAMPLE 109 N-(2-Pyridylmethyl)-4-2-(2-benzyloxy-3-pyridyl)ethyl!benzamide

4- 2-(2-benzyloxy-3-pyridyl)ethyl!benzoic acid (0.48 g, 1.44 mmol) and2-aminomethylpyridine (0.189 g, 1.748 mmol) were dissolved in DMF (20ml) and cooled to 0° C. Triethylamine (0.15 g, 1.5 mmol) was addedfollowed by diphenylphosphorylazide (0.41 g, 1.48 mmol). The reactionmixture was stirred under argon and allowed to warm to ambienttemperature overnight. The reaction was partitioned between EtOAc/water,the organic phase was washed with aqueous sodium bicarbonate, water,dried (MgSO₄) and evaporated. The residue was purified by flashchromatography (MeOH/CH₂ Cl₂) followed by recrystallisation fromEtOAc/hexane and then from EtOH/water to give the title product.

MS (EI+):423 M+!

EXAMPLE 110 N-(3-Pyridyl(methyl)-4-2-benzyloxy-3-pyridyl)ethyl!benzamide

The title product was prepared using a similar method to that of Example109 from the appropriate amine.

MS (EI+):423 M+!

EXAMPLE 111 4- 3-(2-Benzyloxy-3-pyridyl)prop-2-enyl!benzoic acid

(2-(4-Carboxyphenyl)ethyl)triphenylphosphonium bromide (10.9 g, 22.2mmol) was suspended in THF (80 ml) and the flask was flushed with argon.Lithium bis(trimethylsilyl)amide (1M in THF, 48.8 ml) was added dropwiseand the reaction stirred for 1 hour, becoming dark brown. A solution of2-benzyloxy-3-pyridinecarbaldehyde (4.73 g, 22.2 mmol) in THF (20 ml)was added slowly. The reaction was stirred at ambient temperature for 18hours (shielding from light alumimium foil). The reaction mixture wasthen partitioned between Et₂ O/water, the organic layer was washed withwater and the aqueous layers were combined, acidified with HCl andextracted with EtOAc. The organic phase was dried (MgSO₄) and evaporatedand purified by colum chromtagraphy with MeOH/CH₂ Cl₂ to give the titleproduct.

MS:346 M+H! (279 M+H! for Ph₃ PO)

EXAMPLE 112 4- 3-(2-Benzyloxy-3-pyridyl)propyl!benzoic acid

Rhodium-on-alumina (0.69 mg, 5% Ph) was suspended in ethanol (5 ml). Thereaction flask was flushed well with argon. 4-3-(2-Benzyloxy-3-pryidyl)prop-2-enyl!benzoic acid (0.64 g) was dissolvedin ethanol (25 ml) and added to the calalyst. The reaction was placedunder an atmosphere of hydrogen (manometer) and hydrogenation continueduntil the reaction had taken up 1.45 equivalents of hydrogen (11 ml).The reaction mixture was then filtered and evaporated. The materialobtained was purified by chromatography (EtOAc/CH₂ Cl₂) andrecrystallised from ethanol/water to give the title product (0.028 g,4%).

MS (CI+):348 M+H!+

EA:C₂₂ H₂₁ NO₃

Calc 76.1% C, 6.09% H, 4.03% N

Found 75.9% C, 6.1% H, 3.9% N

EXAMPLE 113 4- 3-(3-Benzyloxy-2-pyridyl)prop-2-enyl!benzoic acid

(2-(4-Carboxyphenyl)ethyl)triphenylphosphonium bromide (0.58 g, 1.17mmol) was suspended in THF (7 ml) and lithium bis(trimethylsilyl)amidewas added (1M in THF, 2.46 ml). The reaction mixture turned orange andwas allowed to stir for 1 hour at ambient temperature. A solution of3-benzyloxy-2-pyridinecarbaldehyde (0.25 g, 1.17 mmol) in THF (3.5 ml)was added slowly. The reaction was stirred at ambient temperature for 1hour. The reaction was quenched by the addition of water (8 ml) andether (8 ml). The layers were separated, the ether layer was washed withwater and the as aqueous layers were combined, acidified with 1N HCl andextracted with EtOAc (2×). The organic extracts were dried (MgSO₄) andevaporated to give the title product as a mixture of isomers (2.7 g66%).

MS (CI+):346 M+H!+

EXAMPLE 114 4- 3-(3-Benzyloxy-2-pyridyl)propyl)benzoic acid

Methyl 4- 3-(3-benzyloxy-2-pyridyl)propyl)benzoate (0.3 g, 0.83 mmol)was dissolved in EtOH (3 ml) and treated with 1N NaOH (1.66 ml). Thereaction was stirred at ambient temperature for 18 hours. A solution ofhydrochloric acid (1N, 1.66 ml) was added and the resulting precipitatewas filted and recrystallised from ethanol to give the title product asa white solid (0.054 g).

MS (EI+):348 M+H!+

The starting material was prepared as follows:

4- 3-(3-Benzyloxy-2-pyridyl)prop-2-enyl)benzoic acid (0.1 g, 0.29 mmol)was dissolved in methanol (5 ml) and cooled to 0° C. To the solution wasadded thionyl chloride (0.086 g, 0.73 mmol). The reaction was allowed towarm to ambient temperature and stirred at ambient temperature for 18hours. The reaction mixture was then evaporated, the residue partitionedbetween ethyl acetate and water and the organic phase dried (MgSO₄) andevaporated. The residue was purified by chromatography (SiO₂ EtOAc/CH₂Cl₂) to give methyl 4- 3-(3-benzyloxy-2-pyridyl)prop-2-enyl!benzoate asan oil (0.05 g, 49%).

MS (CI)+:360 M+H!+

Methyl 4- 3-(3-benzyloxy-2-pyridyl)prop-2-enyl!benzoate (1.5 g, 4.2mmol) was dissolved in ethanol (5 ml) and EtOAc (15 ml), treated with10% palladium on carbon (0.15 g) and placed under a hydrogen atmosphere.The mixture was stirred at ambient temperature for 10 hours and filteredand evaporated to give methyl 4- 3-(3-hydroxy-2-pyridyl)propyl!benzoateas a yellow oil (0.88 g, 77%).

MS (CI+):272 M+H!+

Methyl 4- 3-(3-hydroxy-2-pyridyl)propyl!benzoate (0.87 g, 3.2 mmol) wasdissolved in DMF (5 ml) and treated with benzyl bromide (0.66 g, 3.9mmol) and potassium carbonate (0.53 g, 3.8 mmol). The reaction wasstirred at ambient temperature potassium overnight and then partitionedbetween EtOAc/water. The organic phase was washed well with water, dried(MgSO₄) and evaporated. The residue was purified (SiO₂, CH₂ Cl₂ /EtOAc)to give methyl 4- 3-(3-benzyloxy-2-pyridyl)propyl!benzoate as a paleyellow oil.

MS (CI+):362 M+H!+

We claim:
 1. A compound of the formula (I): ##STR251## wherein: A isselected from the group consisting of optionally substituted: phenyl,naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, thienyl,thiadiazolyl and thiazolyl;wherein the --Z-- and --OCH(R³)-- groups arepositioned in a 1,2 relationship to one another on ring carbon atoms;and provided that the ring atom in the 2-position relative to the ringcarbon atom bearing the --OCH(R³)-- group and in the 3-position relativeto the ring carbon atom bearing the --Z--B--R¹ group is unsubstitutedand, when A is naphthyl, either the --Z--B--R¹ group is in the1-position and the --OCH(R³)-- group is in the 2-position of thenaphthyl group and the ring atom in the 3-position is not substituted,or the --Z--B--R¹ -- group is in the 2-position and the --OCH(R³)--group is in the 3-position of the naphthyl group and the ring atom inthe 4-position is not substituted (according to the IUPAC system); B isselected from the group consisting of optionally substituted: phenyl,pyridyl, thiazolyl, thienyl, thiadiazolyl, imidazolyl, oxazolyl,pyrazinyl, pyridazinyl, pyrimidinyl, pyridone, pyridazinone, furan,pyrrole and pyrimidinone; wherein the A--Z-- and --R¹ groups arepositioned in either a 1,3 or a 1,4 relationship to one another on ringcarbon atoms in B in 6 membered rings and in a 1,3 relationship to oneanother on ring carbon atoms in B in 5-membered rings; D is selectedfrom the group consisting of optionally substituted: phenyl, thienyl,furyl, pyridyl, thiazolyl and oxazolyl; R¹ is carboxy, optionallysubstituted tetrazolyl, carboxyC₁₋₄ alkyl, optionally substitutedtetrazolylC₁₋₄ alkyl, hydroxamic acid, sulphonic acid or tetronic acid,or R¹ is of the formula --CONR⁶ R⁷ wherein R⁶ is hydrogen, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₃ alkyl, C₅₋₇ cycloalkenyl or C₅₋₇cycloalkenylC₁₋₃ alkyl and R⁷ is hydrogen, C₁₋₆ alkoxycarbonyl, hydroxyor optionally substituted: C₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, C₁₋₁₀ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₃₋₇ cycloalkylC₂₋₆ alkenyl,C₃₋₇ cycloalkylC₂₋₆ alkynyl, C₅₋₇ cycloalkenyl, C₃₋₇ cycloalkenylC₁₋₆alkyl, C₅₋₇ cycloalkenylC₂₋₆ alkenyl, C₅₋₇ cycloalkenylC₂₋₆ alkynyl, 5-or 6-membered heteroaryl, 5- or 6-membered heteroarylC₁₋₆ alkyl, 5- or6-membered saturated or partially saturated heterocyclyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₆ alkyl, 5-or 6-membered heteroarylium or 5- or 6-membered heteroaryliumC₁₋₆ alkyl;or wherein R⁶ and R⁷ together with the amide nitrogen to which they areattached (NR⁶ R⁷) form an amino acid residue or ester thereof, or R¹ isof the formula --NR⁶ COR⁸ wherein R⁶ is as hereinabove defined and R⁸ isof the formula OR⁹ wherein R⁹ is hydrogen, optionally substituted C₁₋₆alkyl, 5- or 6-membered monocyclic heteroaryl or a 5- or 6-memberedmonocyclic saturated or partially saturated heterocyclyl, or R⁸ is offormula NR¹⁰ R¹¹ wherein R¹⁰ is hydrogen or C₁₋₆ alkyl and R¹¹ isoptionally substituted C₁₋₆ alkyl or R⁸ is optionally substituted C₁₋₆alkyl, or R¹ is of the formula --CONR⁶ SO₂ R¹² wherein R⁶ is ashereinabove defined and R¹² is optionally substituted: C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆alkyl, C₃₋₇ cycloalkylC₂₋₆ alkenyl, C₃₋₇ cycloalkylC₂₋₆ alkynyl, C₅₋₇cycloalkenyl, C₃₋₇ cycloalkenylC₁₋₆ alkyl, C₅₋₇ cycloalkenylC₂₋₆alkenyl, C₅₋₇ cycloalkenylC₂₋₆ alkynyl, 5- or 6-membered heteroaryl, 5-or 6-membered heteroylarylC₁₋₆ alkyl, phenyl, phenylC₁₋₆ alkyl, 5- or6-membered saturated or partially saturated heterocyclyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₆ alkyl, 8-10membered heteroarylC₁₋₆ alkyl or 5- or 6-membered heteroarylC₁₋₄ alkyl,or R¹ is of the formula --CONR⁶ N(R¹⁶)R¹⁷ wherein R⁶ is as hereinabovedefined, R¹⁶ is hydrogen or C₁₋₆ alkyl and R¹⁷ is hydrogen, hydroxy oroptionally substituted: C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₃₋₇ cycloalkylC₂₋₆ alkenyl, C₃₋₇cycloalkylC₂₋₆ alkynyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₆ alkyl,C₅₋₇ cycloalkenylC₂₋₆ alkenyl, C₅₋₇ cycloalkenylC₂₋₆ alkynyl, 5- or6-membered heteroaryl, 5- or 6-membered heteroarylC₁₋₆ alkyl, 5- or6-membered saturated or partially saturated heterocyclyl, 5- or6-membered saturated or partially saturated heterocyclylC₁₋₆ alkyl, orR¹⁶ and R ¹⁷, together with the nitrogen atom to which they areattached, form a 4 to 8-membered saturated or partially saturatedheterocyclic ring or form an amino acid residue or ester thereof, andwherein any 5- or 6-membered heteroaryl group in R¹ is a monocyclic ringsystem having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms areselected from the group consisting of nitrogen, oxygen and sulphur, any5- or 6-membered saturated or partially saturated heterocyclyl group inR¹ is a ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of thering atoms are selected from the group consisting of nitrogen, oxygenand sulphur, any 5- or 6-membered heteroarylium group in R¹ is selectedfrom the group consisting of pyridinium, pyrimidinium, pyrazinium,pyridazinium and imidazolium, any 8-10 membered heteroaryl group in R¹is a bicyclic ring system having 8 to 10 ring atoms wherein 1, 2, 3 or 4ring atoms are selected from the group consisting of nitrogen, oxygenand sulphur, and any 4 to 8-membered saturated or partially saturatedheterocyclic ring in R¹ is a ring system having 4 to 8 ring atomswherein 1, 2 or 3 of the ring atoms are selected from the groupconsisting of nitrogen, oxygen and sulphur; R³ is selected from thegroup consisting of hydrogen and C₁₋₄ alkyl; Z is selected from thegroup of formulae consisting of --(CH(R⁵))_(m) --, --(CHR⁵)_(p) CR⁵ ═CR⁵(CHR⁵)_(q) --, --(CHR⁵)_(r) C(═O)CR⁵ ═CR⁵ (CHR⁵)_(s) -- and --(CHR⁵)_(t)C(═O)(CHR⁵)_(u) --, wherein m is 2, 3 or 4, p and q are independently 0,1 or 2 providing p+q is not greater than 2, one of r and s is 0 and theother is 1 and t and u are independently 0, 1, 2 or 3 providing t+u isnot less than 1 or greater than 3, and R⁵ is selected from the groupconsisting of hydrogen, methyl, ethyl, hydroxy, methoxy and ethoxy; orN-oxides thereof; or S-oxides thereof; or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester or amide thereof; provided thatwhen ring B is optionally substituted phenyl and R¹ is an amide offormula --CONR⁶ R⁷ wherein R is hydrogen or C₁₋₆ alkyl and R⁷ ishydrogen, then ring B bears no more than one optional substituent.
 2. Acompound of the formula (I) according to claim 1 wherein A is optionallysubstituted: phenyl, thienyl, naphthyl or thiadiazolyl.
 3. A compound ofthe formula (I) according to claim 1 wherein B is optionallysubstituted: pyridyl, phenyl, thiazolyl, thienyl, pyrazinyl, oxazolyl,pyridazinyl or 2-pyridone.
 4. A compound of the formula (I) according toclaim 1 wherein D is optionally substituted: phenyl, thienyl or furyl.5. A compound according to claim 1 of the formula (III): ##STR252##wherein R¹,R³, and Z are as defined in claim 1, R¹³ is hydrogen, halo,trifluoromethyl, nitro, hydroxy, amino, C₁₋₄ alkylamino, di C₁₋₆alkyl!amino, cyano, C₁₋₆ alkoxy, carboxy, allyloxy, S(O)_(p) C₁₋₆ alkyl(p is 0, 1 or 2), S(O)_(p) -phenyl (p is 0, 1 or 2), C₁₋₆ alkyl(optionally substituted by hydroxy, C₁₋₄ alkoxy, amino, halo, nitro,S(O)_(p) C₁₋₄ alkyl (p is 0, 1 or 2), S(O)_(p) -phenyl (p is 0, 1 or 2)or cyano), carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄ alkyl)carbamoyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₃ alkyl, C₃₋₇cycloalkylC₂₋₃ alkenyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenylC₂₋₃alkenyl, benzyl, benzoyl, benzyloxy, C₁₋₄ alkoxycarbonylamino, C₁₋₄alkanoylamino, (wherein the alkanoyl group is optionally substituted byhydroxy), C₁₋₄ alkanoyl(N--C₁₋₄ alkyl)amino, wherein the alkanoyl groupis optionally substituted by hydroxy), C₁₋₄ alkanesulphonamido,benzenesulphonamido, aminosulphonyl, C₁₋₄ alkylaminosulphonyl, di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄ alkoxycarbonyl, C₂₋₄ alkanoyloxy, C₁₋₆alkanoyl, formylC₁₋₄ alkyl, trifluoroC₁₋₃ alkylsulphonyl,1-(hydroxyimino)-1-(phenyl)methyl, 1-(C₁₋₄alkoxyimino)-1-(phenyl)methyl, hydroxyiminoC₁₋₆ alkyl, C₁₋₄alkoxyiminoC₁₋₆ alkyl, C₁₋₆ alkylcarbamoylamino, carboxyC₁₋₄ alkoxy,C₂₋₆ alkenyl (substituted by halo), N-(amino)iminoC₁₋₄ alkyl, N-(C₁₋₄alkylamino)iminoC₁₋₄ alkyl, N- di(C₁₋₄ alkyl)amino!iminoC₁₋₄ alkyl,N-(phenyl)aminoiminoC₁₋₄ alkyl, 5-membered heteroaryl containing 1 or 2heteroatoms selected from nitrogen, oxygen and sulphur, tetramethylene,and diradicals of the formula --(CH₂)₃ CO--, --(CH₂)₃ C(═N--OH)-- and--(CH₂)₃ C(═N--OC₁₋₄ alkyl)-- and B is phenyl or hydroxypyridyl.
 6. Acompound of the formula (III) according to claim 5 wherein R³ ishydrogen.
 7. A compound of the formula (III) according to claim 5wherein Z is --(CH₂)₂ --, --(CH₂)₃ -- or --CH═CH--.
 8. A compound of theformula (III) according to claim 5 wherein R¹ is carboxy, tetrazolyl,methanesulphonylaminocarbonyl, benzenesulphonylaminocarbonyl,(optionally substituted on the phenyl ring by nitro, hydroxy, halo,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or trifluoromethyl), or R¹ is ofthe formula --CONR⁶ R⁷ wherein R⁶ is hydrogen or methyl and R⁷ ispropyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-hydroxyethyl, tetrazolyl,tetrazolylmethyl, carboxymethyl, 1-carboxyethyl, 1-carboxypropyl or1-carboxy-3-hydroxypropyl.
 9. A compound according to claim 1 whichis:4- 3-(2-benzyloxy-5-fluorophenyl)butyl!benzoic acid; 4-3-(2-(4-methoxybenzyloxy)phenyl)propyl!benzoic acid;N-(4-nitrobenzenesulphonyl)-4-3-(2-benzyloxyphenyl)propyl!-benzenecarboxamide; 4-3-(2-benzyloxy-5-fluorophenyl)propyl!benzoic acid; 5-4-(2-benzyloxyphenethyl)phenyl!tetrazole; 4-2-benzyloxyphenethyl)-3-fluorobenzoic acid; 5-4-(2-(2-benzyloxyphenyl)ethenyl)phenyl!tetrazole; 4-3-(2-benzyloxy-5-chlorophenyl)propyl!benzoic acid; 4-3-(2-(3-chlorobenzyloxy)phenyl)propyl!benzoic acid; 4-3-(2-benzyloxynaphth-1-yl)propyl!benzoic acid; 4-3-(2-benzyloxy-5-acetylphenyl)propyl!benzoic acid; 4-3-(2-benzyloxy-5-nitrophenyl)propyl!benzoic acid; 4-2-benzyloxy-5-chlorophenethyl!benzoic acid; 5-4-(5-acetyl-2-benzyloxyphenethyl)phenyl!tetrazole; 5-4-(2-benzyloxy-5-bromophenethyl)phenyl!tetrazole; 5-6-(2-benzyloxy-5-bromophenethyl)-1-methyl-1,2-dihydro-2-oxopyridin-3-yl!tetrazole;4- 3-(2-benzyloxy-5-(1-hydroxyiminoethyl)phenyl)propyl!benzoic acid; 4-2-benzyloxyphenethyl!-2-hydroxybenzoic acid; 4-3-(2-benzyloxyphenyl)propyl!-2-hydroxybenzoic acid; 4-3-(2-benzyloxy-5-methylthiophenyl)propyl!benzoic acid; 2-2-benzyloxy-5-bromophenethyl!-3,4-dihydro-3-ethyl-4-oxopyrimidin-5-carboxylicacid; 4- 2-(2-benzyloxyphenyl)ethenyl!-3-bromobenzoic acid; 4-2-(2-benzyloxyphenyl)ethenyl!-3-methoxybenzoic acid; 4-3-(2-benzyloxy-5-(2-methylpropionyl)phenyl)propyl!benzoic acid; 5-4-(2-benzyloxy-5-chlorophenethyl)phenyl!tetrazole;4-(2-benzyloxy-5-bromophenethyl)-2-hydroxybenzoic acid;4-(2-benzyloxyphenethyl)-3-bromobenzoic acid; 4-3-(2-benzyloxy-5-(1-(phenyl)hydroxyiminomethyl)phenyl)propyl!-benzoicacid; 4-(2-benzyloxy-5-bromophenylethyl)-2-methoxybenzoic acid; 4-3-(2-benzyloxy-5-fluorophenyl)propyl!benzoic acid; N-benzenesulphenyl-4-3-(2-benzyloxy-5-chlorophenyl)propyl!-benzenecarboxamide; 4-3-(2-benzyloxy-5-(1-(2-phenylhydrazino)ethyl)phenyl)propyl!benzoic acid;4- 2-(2-benzyloxy-5-methylthiophenyl)ethenyl!-2-hydroxybenzoic acid; 5-4-(2-benzyloxyphenethyl)-3-methoxyphenyl!tetrazole; 4-3-(2-benzyloxyphenyl)propyl!-3-bromobenzoic acid; 5-4-(2-benzyloxyphenethyl)-3-bromophenyl!tetrazole; 4-3-(2-benzyloxyphenyl)propyl!-3-cyanobenzoic acid; 5-4-(3-(2-benzyloxyphenyl)propyl)-3-bromophenyl!tetrazole;4-(2-benzyloxy-5-methylthiophenethyl)-2-hydroxybenzoic acid; 5-4-(3-(2-benzyloxyphenyl)propyl)-3-methoxyphenyl!tetrazole;4-(2-benzyloxy-5-chlorophenethyl)-3-methoxy benzoic acid; 5-4-(2-benzyloxy-5-chlorophenethyl)-3-methoxyphenyl!tetrazole;4-(2-benzyloxy-5-methoxyphenethyl)-2-hydroxybenzoic acid; or4-(2-benzyloxy-5-methylphenethyl)-2-hydroxybenzoic acid; or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition which comprises a compound according to claim 1 and apharmaceutically acceptable carrier.
 11. A method for the treatment ofpain in an animal body in need of such treatment which comprisesadministering to said animal body an effective amount of a compoundaccording claim 1.